Protease inhibitor peptides

ABSTRACT

Analogues of the Kunitz Protease Inhibitor (KPI) domain of amyloid precursor protein bind to and inhibit activity of serine proteases, including kallikrein, plasmin and coagulation factors such as factors VIIa, IXa, Xa, XIa, and XIIa. Pharmaceutical compositions containing the KPI analogues, along with methods for using such compositions, are useful for ameliorating and treating clinical conditions associated with increased serine protease activity, such as blood loss related to cardiopulmonary bypass surgery. Nucleic acid sequences encoding these analogues and systems for expression of the peptides of the invention are provided.

This application is a divisional of application Ser. No. 08/436,555,filed May 8, 1995.

BACKGROUND OF THE INVENTION

The plasma, or serine, proteases of the blood contact system are knownto be activated by interaction with negatively charged surfaces. Forexample, tissue injury during surgery exposes the vascular basementmembrane, causing interaction of the blood with collagen, which isnegatively charged at physiological ph. This induces a cascade ofproteolytic events, leading to production of plasmin, a fibrinolyticprotease, and consequent blood loss.

Perioperative blood loss of this type can be particularly severe duringcardiopulmonary bypass (CPB) surgery, in which the patient's blood flowis diverted to an artificial heart-lung machine. CPB is an essentialcomponent of a number of life-saving surgical procedures. For example,in the United States, it is estimated that 300,000 patients every yearundergo coronary artery bypass grafts involving the use of CPB.

Although necessary and generally safe, CPB is associated with asignificant rate of morbidity, some of which may be attributed to a"whole body inflammatory response" caused by activation of plasmaprotease systems and blood cells through interactions with theartificial surfaces of the heart-lung machine (Butler et al., Ann.Thorac. Surg. 55:552 (1993); Edmunds et al., J. Card. Surg. 8:404(1993)). For example, during extracorporeal circulation, exposure ofblood to negatively charged surfaces of the artificial bypass circuit,e.g., plastic surfaces in the heart-lung machine, results in directactivation of plasma factor XII.

Factor XII is a single-chain 80 kDa protein that circulates in plasma asan inactive zymogen. Contact with negatively charged nonendothelialsurfaces, like those of the bypass circuit, causes surface-bound factorXII to be autoactivated to the active serine protease factor XIIa. SeeColman, Agents Actions Suppl. 42:125 prekallikrein (PK) to activekallikrein, which in turn cleaves more XIIa from XII in a reciprocalactivation reaction that results in a rapid amplification of the contactpathway. Factor XIIa can also activate the first component of complementC1, leading to production of the anaphylatoxin C5a through the classicalcomplement pathway.

The CPB-induced inflammatory response includes changes in capillarypermeability and interstitial fluid accumulation. Cleavage of highmolecular weight kininogen (HK) by activated kallikrein generates thepotent vasodilator bradykinin, which is thought to be responsible forincreasing vascular permeability, resulting in edema, especially in thelung. The lung is particularly susceptible to damage associated withCPB, with some patients exhibiting what has been called "pump lungsyndrome" following bypass, a condition indistinguishable from adultrespiratory distress. See Johnson et al., J. Thorac. Cardiovasc. Surg.107:1193 (1994).

Post-CPB pulmonary injury includes tissue damage thought to be mediatedby neutrophil sequestration and activation in the microvasculature ofthe lung. (Butler et al., supra; Johnson, et al., supra). Activatedfactor XII can itself stimulate neutrophil aggregation. FactorXIIa-generated kallikrein, and complement protein C5a generated byFactor XIIa activation of the complement cascade, both induce neutrophilchemotaxis, aggregation and degranulation. See Edmunds et al., supra(1993). Activated neutrophils may damage tissue through release ofoxygen-derived free-radicals, proteolytic enzymes such as elastase, andmetabolites of arachidonic acid. Release of neutrophil products in thelung can cause changes in vascular tone, endothelial injury and loss ofvascular integrity.

Intrinsic inhibition of the contact system occurs through inhibition ofactivated XIIa by C1-inhibitor (C1-INH). See Colman, supra. During CPB,this natural inhibitory mechanism is overwhelmed by massive activationof plasma proteases and consumption of inhibitors. A potentialtherapeutic strategy for reducing post-bypass pulmonary injury mediatedby neutrophil activation would, therefore, be to block the formation andactivity of the neutrophil agonists kallikrein, factor XIIa, and C5a byinhibition of proteolytic activation of the contact system.

Protease inhibitor therapy which partially attenuates the contact systemis currently employed clinically in CPB. Aprotinin, also known as basicpancreatic protease inhibitor (BPPI), is a small, basic, 58 amino acidpolypeptide isolated from bovine lung. It is a broad spectrum serineprotease inhibitor of the Kunitz type, and was first used during bypassin an attempt to reduce the inflammatory response to CPB. See Butler etal., supra. Aprotinin treatment results in a significant reduction inblood loss following bypass, but does not appear to significantly reduceneutrophil activation. Additionally, since aprotinin is of bovineorigin, there is concern that repeated administration to patients couldlead to the development of an immune response to aprotinin in thepatients, precluding its further use.

The proteases inhibited by aprotinin during CPB appear to include plasmakallikrein and plasmin. (See, e.g., Scott, et al., Blood 69:1431(1987)). Aprotinin is an inhibitor of plasmin (K_(i) of 0.23 nM), andthe observed reduction in blood loss may be due to inhibition offibrinolysis through the blocking of plasmin action. Although aprotinininhibits plasma kallikrein, (K_(i) of 20 nM), it does not inhibitactivated factor XII, and consequently only partially blocks the contactsystem during CPB.

Another attractive protease target for use of protease inhibitors, suchas those of the present invention, is factor XIIa, situated at the veryfirst step of contact activation. By inhibiting the proteolytic activityof factor XIIa, kallikrein production would be prevented, blockingamplification of the contact system, neutrophil activation andbradykinin release. Inhibition of XIIa would also prevent complementactivation and production of C5a. More complete inhibition of thecontact system during CPB could, therefore, be achieved through the useof a better XIIa inhibitor.

Protein inhibitors of factor XIIa are known. For example, active sitemutants of α₁ -antitrypsin that inhibit factor XIIa have been shown toinhibit contact activation in human plasma. See Patston et al., J. Biol.Chem. 265:10786 (1990). The large size and complexity (greater than 400amino acid residues) of these proteins present a significant challengefor recombinant protein production, since large doses will almostcertainly be required during CPB. For example, although it is a potentinhibitor of both kallikrein and plasmin, nearly 1 gram of aprotininmust be infused into a patient to inhibit the massive activation of thekallikrein-kinin and fibrinolytic systems during CPB.

The use of smaller, more potent XIIa inhibitors such as the corn andpumpkin trypsin inhibitors (Wen, et al., Protein Exp. & Purif. 4:215(1993); Pedersen, et al., J. Mol. Biol. 236:385 (1994)) could be morecost-effective than the large α₁ -antitrypsins, but the infusion of highdoses of these non-mammalian inhibitors could result in immunologicreactions in patients undergoing repeat bypass operations. The idealprotein XIIa inhibitor is, therefore, preferably, small, potent, and ofhuman sequence origin.

One candidate for an inhibitor of human origin is found in circulatingisoforms of the human amyloid β-protein precursor (APPI), also known asprotease nexin-2. APPI contains a Kunitz serine protease inhibitordomain known as KPI (Kunitz Protease Inhibitor). See Ponte et al.,Nature, 331:525 (1988); Tanzi et al., Nature 331:528 (1988); Johnstoneet al., Biochem. Biophys. Res. Commun. 163:1248 (1989); Oltersdorf etal., Nature 341:144 (1989). Human KPI shares about 45% amino acidsequence identity with aprotinin. The isolated KPI domain has beenprepared by recombinant expression in a variety of systems, and has beenshown to be an active serine protease inhibitor. See, for example,Sinha, et al., J. Biol. Chem. 265:8983 (1990). The measured in vitroK_(i) of KPI against plasma kallikrein is 45 nM, compared to 20 nM foraprotinin.

Aprotinin, KPI, and other Kunitz-type serine protease inhibitors havebeen engineered by site-directed mutagenesis to improve inhibitoryactivity or specificity. Thus, substitution of Lys¹⁵ of aprotinin witharginine resulted in an inhibitor with a K_(i) of 0.32 nM toward plasmakallikrein, a 100-fold improvement over natural aprotinin. See PCTApplication No. 89/10374. See also Norris et al., Biol. Chem. HoppeSeyler 371:3742 (1990). Alternatively, substitution of position 15 ofaprotinin with valine or substitution of position 13 of KPI with valineresulted in elastase inhibitors with K_(i) s in the 100 pM range,although neither native aprotinin nor native KPI significantly inhibitselastase. See Wenzel et al., in: Chemistry of Peptides and Proteins,Vol. 3, (Walter de Gruyter, Berlin, N.Y., 1986); Sinha et al., supra.Methods for substituting residues 13, 15, 37, and 50 of KPI are shown ingeneral terms in European Patent Application No. 0 393 431, but nospecific sequences are disclosed, and no protease inhibition data aregiven.

Phage display methods have been recently used for preparing andscreening derivatives of Kunitz-type protease inhibitors. See PCTApplication No. 92/15605, which describes specific sequences for 34derivatives of aprotinin, some of which were reportedly active aselastase and cathepsin inhibitors. The amino acid substitutions in thederivatives were distributed throughout almost all positions of theaprotinin molecule.

Phage display methods have also been used to generate KPI variants thatinhibit factor VIIa and kallikrein. See Dennis et al., J. Biol. Chem.269:22129 and 269:22137 (1994). The residues that could be varied in thephage display selection process were limited to positions 9-11, 13-17,32, 36 and 37, and several of those residues were also held constant foreach selection experiment. One of those variants was said to have aK_(i) of 1.2 nM for kallikrein, and had substitutions at positions 9(Thr→Pro), 13 (Arg→Lys), 15 (Met→Leu), and 37 (Gly→Tyr). None of theinhibitors was tested for the ability to inhibit factor XIIa.

It is apparent, therefore, that new protease inhibitors that can bind toand inhibit the activity of serine proteases are greatly to be desired.In particular it is highly desirable to prepare peptides, based on humanpeptide sequences, that can inhibit selected serine proteases such askallikrein; chymotrypsins A and B; trypsin; elastase; subtilisin;coagulants and procoagulants, particularly those in active form,including coagulation factors such as factors VIIa, IXa, Xa, XIa, andXIIa; plasmin; thrombin; proteinase-3; enterokinase; acrosin; cathepsin;urokinase; and tissue plasminogen activator. It is also highly desirableto prepare novel protease inhibitors that can ameliorate one or more ofthe undesirable clinical manifestations associated with enhanced serineprotease activity, for example by reducing pulmonary damage or bloodloss during CPB.

SUMMARY OF THE INVENTION

The present invention relates to peptides that can bind to andpreferably exhibit inhibition of the activity of serine proteases. Thosepeptides can also provide a means of ameliorating, treating orpreventing clinical conditions associated with increased activity ofserine proteases. Particularly, the novel peptides of the presentinvention preferably exhibit a more potent and specific (i.e., greater)inhibitory effect toward serine proteases of interest in comparison toknown serine protease inhibitors. Examples of such proteases include:kallikrein; chymotrypsins A and B; trypsin; elastase; subtilisin;coagulants and procoagulants, particularly those in active form,including coagulation factors such as factors VIIa, IXa, Xa, XIa, andXIIa; plasmin; thrombin; proteinase-3; enterokinase; acrosin; cathepsin;urokinase; and tissue plasminogen activator.

In achieving the inhibition of serine protease activity, the inventionprovides protease inhibitors that can ameliorate one or more of theundesirable clinical manifestations associated with enhanced serineprotease activity, for example, by reducing pulmonary damage or bloodloss during CPB.

The present invention relates to protease inhibitors comprising thefollowing amino acid sequences (SEQ ID NO:1):

X¹ -Val-Cys-Ser-Glu-Gln-Ala-Glu-X² -Gly-X³ -Cys-Arg-Ala-X⁴ -X⁵ -X⁶ -X⁷-Trp-Tyr-Phe-Asp-Val-Thr-Glu-Gly-Lys-Cys-Ala-Pro-Phe-X⁸-Tyr-Gly-Gly-Cys-X⁹ -X¹⁰ -X¹¹ -X¹²-Asn-Asn-Phe-Asp-Thr-Glu-Glu-Tyr-Cys-Met-Ala-Val-Cys-Gly-Ser-Ala-Ile,

wherein: X¹ is selected from Glu-Val-Val-Arg-Glu-, Asp, or Glu; X² isselected from (SEQ ID NO:2) Thr, Val, Ile and Ser; X³ is selected fromPro and Ala; X⁴ is selected from Arg, Ala, Leu, Gly, or Met; X⁵ isselected from Ile, His, Leu, Lys, Ala, or Phe; X⁶ is selected from Ser,Ile, Pro, Phe, Tyr, Trp, Asn, Leu, His, Lys, or Glu; X⁷ is selected fromArg, His, or Ala; X⁸ is selected from Phe, Val, Leu, or Gly; X⁹ isselected from Gly, Ala, Lys, Pro, Arg, Leu, Met, or Tyr; X¹⁰ is selectedfrom Ala, Arg, or Gly; X¹¹ is selected from Lys, Ala, or Asn; and X¹² isselected from Ser, Ala, or Arg.

The invention relates more specifically to protease inhibitorscomprising the following amino acid sequences(SEQ ID NO:1)

X¹ -Val-Cys-Ser-Glu-Gln-Ala-Glu-X² -Gly-X³ -Cys-Arg-Ala-X⁴ -X⁵ -X⁶ -X⁷-Trp-Tyr-Phe-Asp-Val-Thr-Glu-Gly-Lys-Cys-Ala-Pro-Phe-X⁸-Tyr-Gly-Gly-Cys-X⁹ -X¹⁰ -X¹¹ -X¹²-Asn-Asn-Phe-Asp-Thr-Glu-Glu-Tyr-Cys-Met-Ala-Val-Cys-Gly-Ser-Ala-Ile,

wherein X¹ is selected from Glu-Val-Val-Arg-Glu-, Asp, or Glu; X² isselected from Thr, Val, Ile and Ser; X³ is selected from Pro and Ala; X⁴is selected from Arg, Ala, Leu, Gly, or Met; X⁵ is selected from Ile,His, Leu, Lys, Ala, or Phe; X⁶ is selected from Ser, Ile, Pro, Phe, Tyr,Trp, Asn, Leu, His, Lys, or Glu; X⁷ is selected from Arg, His, or Ala;X⁸ is selected from Phe, Val, Leu, or Gly; X⁹ is selected from Gly, Ala,Lys, Pro, Arg, Leu, Met, or Tyr; X¹⁰ is selected from Ala, Arg, or Gly;X¹¹ is selected from Lys, Ala, or Asn; X¹² is selected from Ser, Ala, orArg; provided that when X⁴ is Arg, X⁶ is Ile; when X⁹ is Arg, X⁴ is Alaor Leu; when X⁹ is Tyr, X⁴ is Ala or X⁵ is His; and either X⁵ is notIle; or X⁶ is not Ser; or X⁹ is not Leu, Phe, Met, Tyr, or Asn; or X¹⁰is not Gly; or X¹¹ is not Asn; or X¹² is not Arg.

Another aspect of this invention provides protease inhibitors wherein atleast two amino acid residues selected from the group consisting of X⁴,X⁵, X⁶, and X⁷ defined above differ from the residues found in thenaturally occurring sequence of KPI. Another aspect of this inventionprovides protease inhibitors wherein X¹ is Asp or Glu, X² is Thr, X³ isPro, and X¹² is Ser. Yet another aspect of this invention providesprotease inhibitors wherein X¹ is Glu, X² is Thr, X³ is Pro, X⁴ is Met,X⁵ is Ile, X⁶ is Ser, X⁷ is Arg, x⁸ is Phe, X⁹ is Gly, X¹⁰ is Gly, andX¹¹ is Asn. Another aspect of this invention provides proteaseinhibitors wherein X¹ is Asp, X² is Thr, X³ is Pro, X⁴ is Arg, X⁵ isIle, X⁶ is Ile, X⁷ is Arg, x⁸ is Val, X⁹ is Arg, X¹⁰ is Ala, and X¹¹ isLys. Another aspect of this invention provides protease inhibitorswherein X¹ (SEQ ID NO:2) is Glu-Val-Val-Arg-Glu-, X² is Thr, X³ is Pro,X⁴ is Met, X⁵ is Ile, X⁶ is Ser, X⁷ is Arg, x⁸ is Phe, X⁹ is Gly, X¹⁰ isGly, X¹¹ is Asn, and X¹² is Ala. Another aspect of this inventionprovides protease inhibitors wherein X¹ (SEQ ID NO:2) isGlu-Val-Val-Arg-Glu-, X² is Thr, X³ is Pro, X⁴ is Met, X⁵ is Ile, X⁶ isSer, X⁷ is Arg, x⁸ is Phe, X⁹ is Gly, X¹⁰ is Gly, X¹¹ is Ala, and X¹² isArg. Another aspect of this invention provides protease inhibitorswherein X¹ is Glu, X² is Thr, X³ is Pro, X⁴ is Met, X⁵ is Ile, X⁶ isSer, X⁷ is Arg, x⁸ is Phe, X⁹ is Gly, X¹⁰ is Ala, X¹¹ is Asn, and X¹² isArg. Another aspect of this invention provides protease inhibitorswherein X¹ (SEQ ID NO:2) is Glu-Val-Val-Arg-Glu-, X² is Thr, X³ is Pro,X⁴ is Met, X⁵ is Ile, X⁶ is Ser, X⁷ is Arg, x⁸ is Phe, X⁹ is Gly, X¹⁰ isArg, X¹¹ is Asn, and X¹² is Arg. Another aspect of this inventionprovides protease inhibitors wherein X¹ is Glu-Val-Val-Arg-Glu-(SEQ IDNO:2), X² is Thr, X³ is Pro, X⁴ is Met, X⁵ is Ile, X⁶ is Ser, X⁷ is Arg,x⁸ is Val, Leu, or Gly, X⁹ is Gly, X¹⁰ is Gly, X¹¹ is Asn, and X¹² isArg. Another aspect of this invention provides protease inhibitorswherein X¹ is Glu-Val-Val-Arg-Glu-(SEQ ID NO:2), X² is Thr, X³ is Pro,X⁴ is Met, X⁵ is Ile, X⁶ is Ser, X⁷ is Ala, x⁸ is Phe, X⁹ is Gly, X¹⁰ isGly, X¹¹ is Asn, and X¹² is Arg. Another aspect of this inventionprovides protease inhibitors wherein X¹ is Glu-Val-Val-Arg-Glu-(SEQ IDNO:2), X² is Thr, Val, or Ser, X³ is Pro, X⁴ is Ala or Leu, X⁵ is Ile,X⁶ is Tyr, X⁷ His, X⁸ is Phe, X⁹ is Gly, X¹⁰ is Gly, X¹¹ is Ala, and X¹²is Arg.

Yet another aspect of this invention provides protease inhibitorswherein X² is Thr, and X⁴ is Ala. Another aspect of this inventionprovides protease inhibitors wherein X² is Thr, and X⁴ is Leu. Anotheraspect of this invention provides protease inhibitors wherein X² is Val,and X⁴ is Ala. Another aspect of this invention provides proteaseinhibitors wherein X² is Ser, and X⁴ is Ala. Another aspect of thisinvention provides protease inhibitors wherein X² is Val, and X⁴ is Leu.Another aspect of this invention provides protease inhibitors wherein X²is Ser, and X⁴ is Leu.

Yet another aspect of this invention provides protease inhibitorswherein X¹ is Glu-Val-Val-Arg-Glu-(SEQ ID NO:2), X² is Thr, X³ is Pro,X⁴ is Leu, X⁵ is Phe, X⁶ is Lys, X⁷ is Arg, X⁸ is Phe, X⁹ is Gly, X¹⁰ isGly, X¹¹ is Ala, and X¹² is Arg. Another aspect of this inventionprovides protease inhibitors wherein X¹ is Glu-Val-Val-Arg-Glu-(SEQ IDNO:2), X² is Thr, X³ is Pro, X⁴ is Leu, X⁵ is Phe, X⁶ is Lys, X⁷ is Arg,X⁸ is Phe, X⁹ is Tyr, X¹⁰ is Gly, X¹¹ is Ala, and X¹² is Arg. Anotheraspect of this invention provides protease inhibitors wherein X¹ isGlu-Val-Val-Arg-Glu-(SEQ ID NO:2), X² is Thr, X³ is Pro, X⁴ is Leu, X⁵is Phe, X⁶ is Lys, X⁷ is Arg, X⁸ is Phe, X⁹ is Leu, X¹⁰ is Gly, X¹¹ isAla, and X¹² is Arg.

A further aspect of this invention provides an isolated DNA moleculecomprising a DNA sequence encoding a protease inhibitor of theinvention. Another aspect of this invention provides an isolated DNAmolecule comprising a DNA sequence encoding the protease inhibitor thatfurther comprises an isolated DNA molecule operably linked to aregulatory sequence that controls expression of the coding sequence ofthe protease inhibitor in a host cell. Another aspect of this inventionprovides an isolated DNA molecule comprising a DNA sequence encoding theprotease inhibitor operably linked to a regulatory sequence thatcontrols expression of the coding sequence of the protease inhibitor ina host cell that further comprises a DNA sequence encoding a secretorysignal peptide. That secretory signal peptide may preferably comprisethe signal sequence of yeast alpha-mating factor. Another aspect of thisinvention provides a host cell transformed with any of the DNA moleculesdefined above. Such a host cell may preferably comprise E. coli or ayeast cell. When such a host cell is a yeast cell, the yeast cell maypreferably be Saccharomyces cerevisiae.

Another aspect of this invention provides a method for producing aprotease inhibitor of the present invention, comprising the steps ofculturing a host cell as defined above and isolating and purifying saidprotease inhibitor.

A further aspect of this invention provides a pharmaceuticalcomposition, comprising a protease inhibitor of the present inventiontogether with a pharmaceutically acceptable sterile vehicle.

An additional aspect of this invention provides a method of treatment ofa clinical condition associated with increased activity of one or moreserine proteases, comprising administering to a patient suffering fromsaid clinical condition an effective amount of a pharmaceuticalcomposition comprising a protease inhibitor of the present inventiontogether with a pharmaceutically acceptable sterile vehicle. That methodof treatment may preferably be used to treat the clinical condition ofblood loss during surgery.

Yet another aspect of this invention provides a method for inhibitingthe activity of serine proteases of interest in a mammal comprisingadministering a therapeutically effective dose of a pharmaceuticalcomposition comprising a protease inhibitor of the present inventiontogether with a pharmaceutically acceptable sterile vehicle.

Another aspect of this invention provides a method for inhibiting theactivity of serine proteases of interest in a mammal comprisingadministering a therapeutically effective dose of a pharmaceuticalcomposition comprising a protease inhibitor of the present inventiontogether with a pharmaceutically acceptable sterile vehicle, whereinsaid serine proteases are selected from the group consisting of:kallikrein; chymotrypsins A and B; trypsin; elastase; subtilisin;coagulants and procoagulants, particularly those in active form,including coagulation factors such as factors VIIa, IXa, Xa, XIa, andXIIa; plasmin; thrombin; proteinase-3; enterokinase; acrosin; cathepsin;urokinase; and tissue plasminogen activator.

A further aspect of this invention relates to protease inhibitorscomprising the following amino acid sequences(SEQ ID NO:3):

X¹ -Val-Cys-Ser-Glu-Gln-Ala-Glu-Thr-Gly-Pro-Cys-Arg-Ala-X² -X³ -X⁴-Arg-Trp-Tyr-Phe-Asp-Val-Thr-Glu-Gly-Lys-Cys-Ala-Pro-Phe-Phe-Tyr-Gly-Gly-Cys-X⁵-Gly-Asn-Arg-Asn-Asn-Phe-Asp-Thr-Glu-Glu-Tyr-Cys-Met-Ala-Val-Cys-Gly-Ser-Ala-Ile,

wherein X¹ (SEQ ID NO:2) is selected from Glu-Val-Val-Arg-Glu-, Asp, orGlu; X² is selected from Ala, Leu, Gly, or Met; X³ is selected from Ile,His, Leu, Lys, Ala, or Phe; X⁴ is selected from Ser, Ile, Pro, Phe, Tyr,Trp, Asn, Leu, His, Lys, or Glu; X⁵ is selected from Gly, Ala, Lys, Pro,Arg, Leu, Met, or Tyr; provided that when X⁵ is Arg, X² is Ala or Leu;when X⁵ is Tyr, X² is Ala or X³ is His; and either X³ is not Ile; or X⁴is not Ser; or X⁵ is not Leu, Phe, Met, Tyr, or Asn. Another aspect ofthis invention provides a protease inhibitor as defined above wherein X¹is Glu, X² is Met, X³ is Ile, X⁴ is Ile, and X⁵ is Gly.

The invention also relates more specifically to protease inhibitorscomprising the following amino acid sequences(SEQ ID NO:4):

Glu-Val-Val-Arg-Glu-Val-Cys-Ser-Glu-Gln-Ala-Glu-Thr-Gly-Pro-Cys-Arg-Ala-X.sup.1-X² -X³ -Arg-Trp-Tyr-Phe-Asp-Val-Thr-Glu-Gly-Lys-Cys-Ala-Pro-Phe-Phe-Tyr-Gly-Gly-Cys-X⁴-Gly-Asn-Arg-Asn-Asn-Phe-Asp-Thr-Glu-Glu-Tyr-Cys-Met-Ala-Val-Cys-Gly-Ser-Ala-Ile,

wherein X¹ is selected from Ala, Leu, Gly, or Met; X² is selected fromIle, His, Leu, Lys, Ala, or Phe; X³ is selected from Ser, Ile, Pro, Phe,Tyr, Trp, Asn, Leu, His, Lys, or Glu; X⁴ is selected from Gly, Arg, Leu,Met, or Tyr; provided that when X¹ is Ala, X² is Ile, His, or Leu; whenX¹ is Leu, X² is le or His; when X¹ is Leu and X² is Ile, X³ is not Ser;when X¹ is Gly, X² is Ile; when X⁴ is Arg, X¹ is Ala or Leu; when X⁴ isTyr, X¹ is Ala or X² is His; and either X¹ is not Met, or X² is not Ile,or X³ is not Ser, or X⁴ is not Gly.

A further aspect of this invention provides a protease inhibitor asdefined above wherein X¹ is Met, X³ is Ser, and X⁴ is Gly. Anotheraspect of this invention provides a protease inhibitor wherein X² isselected from His, Ala, Phe, Lys, and Leu. Another aspect of thisinvention provides a protease inhibitor wherein X² is His. Anotheraspect of this invention provides a protease inhibitor wherein X² isAla. Another aspect of this invention provides a protease inhibitorwherein X² is Phe. Another aspect of this invention provides a proteaseinhibitor wherein X² is Lys. Another aspect of this invention provides aprotease inhibitor wherein X² is Leu. Another aspect of this inventionprovides a protease inhibitor wherein X¹ is Met, X² is Ile, and X⁴ isGly.

Yet another aspect of this invention provides a protease inhibitorwherein X³ is Ile. Another aspect of this invention provides a proteaseinhibitor wherein X³ is Pro. Another aspect of this invention provides aprotease inhibitor wherein X³ is Phe. Another aspect of this inventionprovides a protease inhibitor wherein X³ is Tyr. Another aspect of thisinvention provides a protease inhibitor wherein X³ is Trp. Anotheraspect of this invention provides a protease inhibitor wherein X³ isAsn. Another aspect of this invention provides a protease inhibitorwherein X³ is Leu.

An additional aspect of this invention provides a protease inhibitorwherein X³ is Lys. Another aspect of this invention provides a proteaseinhibitor wherein X³ is His. Another aspect of this invention provides aprotease inhibitor wherein X³ is Glu. Another aspect of this inventionprovides a protease inhibitor wherein X¹ is Ala. Another aspect of thisinvention provides a protease inhibitor wherein X² is Ile. Anotheraspect of this invention provides a protease inhibitor wherein X³ isPhe, and X⁴ is Gly. Another aspect of this invention provides a proteaseinhibitor wherein X³ is Tyr, and X⁴ is Gly. Another aspect of thisinvention provides a protease inhibitor wherein X³ is Trp, and X⁴ isGly.

Yet another other aspect of this invention provides a protease inhibitorwherein X³ is Ser or Phe, and X⁴ is Arg or Tyr. Another aspect of thisinvention provides a protease inhibitor wherein X² is His or Leu, X³ isPhe, and X⁴ is Gly. Another aspect of this invention provides a proteaseinhibitor wherein X¹ is Leu. Another aspect of this invention provides aprotease inhibitor wherein X² is His, X³ is Asn or Phe, and X⁴ is Gly.Another aspect of this invention provides a protease inhibitor whereinX² is Ile, X³ is Pro, and X⁴ is Gly. Another aspect of this inventionprovides a protease inhibitor wherein X¹ is Gly, X² is Ile, X³ is Tyr,and X⁴ is Gly. Another aspect of this invention provides a proteaseinhibitor wherein X¹ is Met, X² is His, X³ is Ser, and X⁴ is Tyr.

Additionally, another aspect of this invention relates to proteaseinhibitors comprising the following amino acid sequences(SEQ ID NO:5):

X¹ -Val-Cys-Ser-Glu-Gln-Ala-Glu-X² -Gly-Pro-Cys-Arg-Ala-X³ -X⁴ -X⁵ -X⁶-Trp-Tyr-Phe-Asp-Val-Thr-Glu-Gly-Lys-Cys-Ala-Pro-Phe-Phe-Tyr-Gly-Gly-Cys-X⁷-Gly-Asn-Arg-Asn-Asn-Phe-Asp-Thr-Glu-Glu-Tyr-Cys-Met-Ala-Val-Cys-Gly-Ser-Ala-Ile,

wherein X¹ is selected from Glu-Val-Val-Arg-Glu-(SEQ ID NO:2), Asp, orGlu; X² is selected from Thr, Val, Ile and Ser; X³ is selected from Arg,Ala, Leu, Gly, or Met; X⁴ is selected from Ile, His, Leu, Lys, Ala, orPhe; X⁵ is selected from Ser, Ile, Pro, Phe, Tyr, Trp, Asn, Leu, His,Lys, or Glu; X⁶ is selected from Arg, His, or Ala; and X⁷ is selectedfrom Gly, Ala, Lys, Pro, Arg, Leu, Met, or Tyr.

Another aspect of this invention provides a protease inhibitor asdefined above wherein at least two amino acid residues selected from thegroup consisting of X³, X⁴, X⁵, and X⁶ differ from the residues found inthe naturally occurring sequence of KPI. Another aspect of thisinvention provides a protease inhibitor wherein X¹ (SEQ ID NO:2) isGlu-Val-Val-Arg-Glu-, X² is Thr, Val, or Ser, X³ is Ala or Leu, X⁴ isIle, X⁵ is Tyr, X⁶ is His and X⁷ is Gly. Another aspect of thisinvention provides a protease inhibitor wherein X² is Thr, and X³ isAla. Another aspect of this invention provides a protease inhibitorwherein X² is Thr, and X³ is Leu. Another aspect of this inventionprovides a protease inhibitor wherein X² is Val, and X³ is Ala. Anotheraspect of this invention provides a protease inhibitor wherein X² isSer, and X³ is Ala. Another aspect of this invention provides a proteaseinhibitor wherein X² is Val, and X³ is Leu. Another aspect of thisinvention provides a protease inhibitor wherein X² is Ser, and X³ isLeu. Another aspect of this invention provides a protease inhibitorwherein X¹ (SEQ ID NO:2) is Glu-Val-Val-Arg-Glu-, X² is Thr, X³ is Leu,X⁴ is Phe, X⁵ is Lys, X⁶ is Arg and X⁷ is Gly. Another aspect of thisinvention provides a protease inhibitor wherein X¹ (SEQ ID NO:2) isGlu-Val-Val-Arg-Glu-, X² is Thr, X³ is Leu, X⁴ is Phe, X⁵ is Lys, X⁶ isArg and X⁷ is Tyr. Another aspect of this invention provides a proteaseinhibitor wherein X¹ (SEQ ID NO:2) is Glu-Val-Val-Arg-Glu-, X² is Thr,X³ is Leu, X⁴ is Phe, X⁵ is Lys, X⁶ is Arg and X⁷ is Leu.

Other objects, features and advantages of the present invention willbecome apparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples, while indicating preferred embodiments of the invention, aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the strategy for the construction of plasmid pTW10:KPI.

FIG. 2 shows the sequence (SEQ ID NOS:74 and 75) of the synthetic genefor KPI (1→57) fused to the bacterial phoA secretory signal sequence.

FIG. 3 (SEQ ID NOS15-18, respectfully) shows the strategy forconstruction of plasmid pKPI-61.

FIG. 4 (SEQ ID NOS76 and 77) shows the 192 bp XbaI-HindIII syntheticgene fragment encoding KPI (1→57) and four amino acids from yeastalpha-mating factor.

FIG. 5 (SEQ ID NOS78 and 79) shows the synthetic 201 bp XbaI-HindIIIfragment encoding KPI (-4→57) in PKPI-61.

FIG. 6 shows the strategy for the construction of plasmid pTW113.

FIG. 7 (SEQ ID NOS80 and 81) shows plasmid PTW113, encoding the 445 bpsynthetic gene for yeast alpha-factor-KPI (-4→57) fusion.

FIG. 8 (SEQ ID NO:79) shows the amino acid sequence for KPI (-4→57).

FIG. 9 (SEQ ID NOS25 and 26) shows the strategy for constructing plasmidpTW6165.

FIG. 10 (SEQ ID NOS82 and 83) shows plasmid, PTW6165, encoding the 445bp synthetic gene for alpha-factor-KPI(-4→57; M15A, S17W) fusion.

FIG. 11 (SEQ ID NOS25-42, respectfully) shows the sequences of theannealed oligonucleotide pairs used to construct plasmids PTW6165,pTW6166, pTW6175, pBG028, pTW6183, pTW6184, pTW6185, pTW6173, andpTW6174.

FIG. 12 (SEQ ID NOS84 and 85) shows the sequence of plasmid PTW6166encoding the fusion of yeast alpha-factor and KPI(-4→57; M15A, S17Y).

FIG. 13 (SEQ ID NOS86 and 87) shows the sequence of plasmid PTW6175encoding the fusion of yeast alpha-factor and KPI(-4→57; M15L, S17F).

FIG. 14 (SEQ ID NOS88 and 89) shows the sequence of plasmid PBG028encoding the fusion of yeast alpha-factor and KPI(-4→57; M15L, S17Y).

FIG. 15 (SEQ ID NOS90 and 91) shows the sequence of plasmid PTW6183encoding the fusion of yeast alpha-factor and KPI(-4→57; I16H, S17F).

FIG. 16 (SEQ ID NOS92 and 93) shows the sequence of plasmid PTW6184encoding the fusion of yeast alpha-factor and KPI(-4→57; I16H, S17Y).

FIG. 17 (SEQ ID NOS94 and 95) shows the sequence of plasmid PTW6185encoding the fusion of yeast alpha-factor and KPI(-4→57; I16H, S17W).

FIG. 18 (SEQ ID NOS96 and 97) shows the sequence of plasmid PTW6173encoding the fusion of yeast alpha-factor and KPI(-4→57; M15A, I16H).

FIG. 19 (SEQ ID NOS98 and 99)shows the sequence of plasmid PTW6174encoding the fusion of yeast alpha-factor and KPI(-4→57; M15L, I16H).

FIG. 20 shows the amino acid sequence (SEQ ID NO:83) of KPI (-4→57;M15A, S17W).

FIG. 21 shows the amino acid sequence (SEQ ID NO:85) of KPI (-4→57;M15A, S17Y).

FIG. 22 shows the amino acid sequence (SEQ ID NO:87) of KPI (-4→57;M15L, S17F).

FIG. 23 shows the amino acid sequence (SEQ ID NO:89) of KPI (-4→57;M15L, S17Y).

FIG. 24 shows the amino acid sequence (SEQ ID NO:91) of KPI (-4→57;I16H, S17F).

FIG. 25 shows the amino acid sequence (SEQ ID NO:93) of KPI (-4→57;I16H, S17Y).

FIG. 26 shows the amino acid sequence (SEQ ID NO:95) of KPI (-4→57;I16H, S17W).

FIG. 27 shows the amino acid sequence (SEQ ID NO:107) of KPI (-4→57;M15A, S17F).

FIG. 28 shows the amino acid sequence (SEQ ID NO:97) of KPI (-4→57;M15A, I16H).

FIG. 29 shows the amino acid sequence (SEQ ID NO:99) of KPI (-4→57;M15L, I16H).

FIG. 30 (SEQ ID NOS45-48, respectfully) shows the construction ofplasmid pSP26:Amp:F1.

FIG. 31 shows the construction of plasmid pgIII.

FIG. 32 shows the construction of plasmid pPhoA:KPI:gIII.

FIG. 33 shows the construction of plasmid pLG1.

FIG. 34 (SEQ ID NOS55 and 56) shows the construction of plasmid pAL51.

FIG. 35 shows the construction of plasmid pAL53.

FIG. 36 shows the construction of plasmid PSP26:Amp:F1:PhoA:KPI:gIII.

FIG. 37 shows the construction of plasmid pDW1 #14.

FIG. 38 (SEQ ID NOS100 and 101) shows the coding region for the fusionof phoA-KPI (1→55)-geneIII.

FIG. 39 shows the construction of plasmid PDW1 14-2.

FIG. 40 shows the construction of KPI Library 16-19.

FIG. 41 (SEQ ID NOS102 and 103) shows the expression unit encoded by themembers of KPI Library 16-19.

FIG. 42 (SEQ ID NOS104 and 105) shows the phoA-KPI(1→55)-geneIII regionencoded by the most frequently occurring randomized KPI region.

FIG. 43 shows the construction of pDD185 KPI (-4→57; M15A, S17F).

FIG. 44 (SEQ ID NOS106 and 107) shows the sequence of alpha-factor fusedto KPI (-4→57; M15A, S17F).

FIG. 45 shows the inhibition constants (K_(i) s) determined for purifiedKPI variants against the selected serine proteases kallikrein, factorXa, and factor XIIa.

FIG. 46 (SEQ ID NOS108-228, respectfully) shows the inhibition constants(K_(i) s) determined for KPI variants against kallikrein, plasmin, andfactors Xa, XIa, and XIIa.

FIG. 47 shows the post-surgical blood loss in pigs in the presence (KPI)and absence (NS) of KPI 185-1 (M15A, S17F).

FIG. 48 shows the post-surgical hemoglobin loss in pigs in the presence(KPI) and absence (NS) of KPI 185-1 (M15A, S17F).

FIG. 49 shows the oxygen tension in the presence and absence of KPI,before CPB, immediately after CPB, and at 60 and 180 minutes after theend of CPB.

FIG. 50 summarizes the results shown in FIGS. 47-49.

DETAILED DESCRIPTION

The present invention provides peptides that can bind to and preferablyinhibit the activity of serine proteases. These inhibitory peptides canalso provide a means of ameliorating, treating or preventing clinicalconditions associated with increased activity of serine proteases. Thenovel peptides of the present invention preferably exhibit a more potentand specific (i.e., greater) inhibitory effect toward serine proteasesof interest than known serine protease inhibitors. Examples of suchproteases include: kallikrein; chymotrypsins A and B; trypsin; elastase;subtilisin; coagulants and procoagulants, particularly those in activeform, including coagulation factors such as factors VIIa, IXa, Xa, XIa,and XIIa; plasmin; thrombin; proteinase-3; enterokinase; acrosin;cathepsin; urokinase; and tissue plasminogen activator.

Peptides of the present invention may be used to reduce the tissuedamage caused by activation of the proteases of the contact pathway ofthe blood during surgical procedures such as cardiopulmonary bypass(CPB). Inhibition of contact pathway proteases reduces the "whole bodyinflammatory response" that can accompany contact pathway activation,and that can lead to tissue damage, and possibly death. The peptides ofthe present invention may also be used in conjunction with surgicalprocedures to reduce activated serine protease-associated perioperativeand postoperative blood loss. For instance, perioperative blood loss ofthis type may be particularly severe during CPB surgery. Pharmaceuticalcompositions comprising the peptides of the present invention may beused in conjunction with surgery such as CPB; administration of suchcompositions may occur preoperatively, perioperatively orpostoperatively. Examples of other clinical conditions associated withincreased serine protease activity for which the peptides of the presentinvention may be used include: CPB-induced inflammatory response;post-CPB pulmonary injury; pancreatitis; allergy-induced proteaserelease; deep vein thrombosis; thrombocytopenia; rheumatoid arthritis;adult respiratory distress syndrome; chronic inflammatory bowel disease;psoriasis; hyperfibrinolytic hemorrhage; organ preservation; woundhealing; and myocardial infarction. Other examples of preferable uses ofthe peptides of the present invention are described in U.S. Pat. No.5,187,153.

The invention is based upon the novel substitution of amino acidresidues in the peptide corresponding to the naturally occurring KPIprotease inhibitor domain of human amyloid β-amyloid precursor protein(APPI). These substitutions produce peptides that can bind to serineproteases and preferably exhibit an inhibition of the activity of serineproteases. The peptides also preferably exhibit a more potent andspecific serine protease inhibition than known serine proteaseinhibitors. In accordance with the invention, peptides are provided thatmay exhibit a more potent and specific inhibition of one or more serineproteases of interest, e.g., kallikrein, plasmin and factors Xa, XIa,XIIa, and XIIa.

The present invention also includes pharmaceutical compositionscomprising an effective amount of at least one of the peptides of theinvention, in combination with a pharmaceutically acceptable sterilevehicle, as described in REMINGTON'S PHARMACEUTICAL SCIENCES: DRUGRECEPTORS AND RECEPTOR THEORY, (18th ed.), Mack Publishing Co., Easton,Pa. (1990).

A. Selection of Sequences of KPI Variants The sequence of KPI is shownin Table 1. Table 2 shows a comparison of this sequence with that ofaprotinin, with which it shares about 45% sequence identity. Thenumbering convention for KPI shown in Table 1 and used hereinafterdesignates the first glutamic acid residue of KPI as residue 1. Thiscorresponds to residue number 3 using the standard numbering conventionfor aprotinin.

The crystal structure for KPI complexed with trypsin has beendetermined. See Perona et al., J. Mol. Biol. 230:919 (1993). Thethree-dimensional structure reveals two binding loops within KPI thatcontact the protease. The first loop extends from residue Thr⁹ to Ile¹⁶,and the second loop extends from residue Phe³² to Gly³⁷. The twoprotease binding loops are joined through the disulfide bridge extendingfrom Cys¹² to Cys³⁶. KPI contains two other disulfide bridges, betweenCys³ and Cys⁵³, and between Cys²⁸ to Cys⁴⁹.

This structure was used as a guide to inform our strategy for making theamino acid residue substitutions that will be most likely to affect theprotease inhibitory properties of KPI. Our examination of the structureindicated that certain amino acid residues, including residues 9, 11,13-18, 32, and 37-40, appear to be of particular significance indetermining the protease binding properties of the KPI peptide. In apreferred embodiment of the invention two or more of those KPI peptideresidues are substituted; such substitutions preferably occurring amongresidues 9, 11, 13-18, 32, and 37-40. In particular, we found that thosesubstituted peptides, including peptides comprising substitutions of atleast two of the four residues at positions 15-18, may exhibit morepotent and specific serine protease inhibition toward selected serineproteases of interest than exhibited by the natural KPI peptide domain.Such substituted peptides may further comprise one or more additionalsubstitutions at residues 9, 11, 13, 14, 32 and 37-40; in particular,such peptides may further comprise a substitution at positions 9 or 37.In particular, the peptides of the present invention preferably exhibita greater potency and specificity for inhibiting one or more serineproteases of interest (e.g., kallikrein, plasmin and factors VIIa, IXa,Xa, XIa, and XIIa) than the potency and specificity exhibited by nativeKPI or other known serine protease inhibitors. That greater potency andspecificity may be manifested by the peptides of the present inventionby exhibiting binding constants for serine proteases of interest thatare less than the binding constants exhibited by native KPI, or otherknown serine protease inhibitors, for such proteases.

By way of example, and as set forth in greater detail below, the serineprotease inhibitory properties of peptides of the present invention weremeasured for the serine proteases of interest--kallikrein, plasmin andfactors Xa, XIa, and XIIa. Methodologies for measuring the inhibitoryproperties of the KPI variants of the present invention are known tothose skilled in the art, e.g., by determining the inhibition constantsof the variants toward serine proteases of interest, as described inExample 4, infra. Such studies measure the ability of the novel peptidesof the present invention to bind to one or more serine proteases ofinterest and to preferably exhibit a greater potency and specificity forinhibiting one or more serine protease of interest than known serineprotease inhibitors such as native KPI.

The ability of the peptides of the present invention to bind one or moreserine proteases of interest, particularly the ability of the peptidesto exhibit such greater potency and specificity toward serine proteasesof interest, manifest the clinical and therapeutic applications of suchpeptides. The clinical and therapeutic efficacy of the peptides of thepresent invention can be assayed by in vitro and in vivo methodologiesknown to those skilled in the art, e.g., as described in Example 5,infra.

                                      TABLE 1    __________________________________________________________________________    (SEQ ID NO:6) SEQUENCE OF KPI    __________________________________________________________________________       1                 10                  20                  30    V R E V C S E Q A E T G P C R A M I S R W Y F D V T E G K C A P                      40                 50    F F Y G G C G G N R N N F D T E E Y C M A V C G S A I    __________________________________________________________________________

                                      TABLE 2    __________________________________________________________________________    (SEQ ID NOS 6 and 7)    COMPARISON OF KPI AND APROTININ SEQUENCES    __________________________________________________________________________           1            10        20  30        40        50    KPI:        VREVCSEQAETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVCGSAI            | |   ||||        | | |       | |        | ||||   |.vertl        ine.||   | ||  |        | |    BPTI:        RPDFCLEPPYTGPCKARIIRYFYNAKAGLCQTFVYGGCRAKRNNFKSAEDCMRTCGGA        1       10        20        30        40        50    __________________________________________________________________________

B. Methods of Producing KPI Variants

The peptides of the present invention can be created by synthetictechniques or recombinant techniques which employ genomic or cDNAcloning methods.

1. Production by Chemical Synthesis

Peptides of the present invention can be routinely synthesized usingsolid phase or solution phase peptide synthesis. Methods of preparingrelatively short peptides such as KPI by chemical synthesis are wellknown in the art. KPI variants could, for example be produced bysolid-phase peptide synthesis techniques using commercially availableequipment and reagents such as those available from Milligen (Bedford,Mass.) or Applied Biosystems-Perkin Elmer (Foster City, Calif.).Alternatively, segments of KPI variants could be prepared by solid-phasesynthesis and linked together using segment condensation methods such asthose described by Dawson et al., Science 266:776 (1994). Duringchemical synthesis of the KPI variants, substitution of any amino acidis achieved simply by replacement of the residue that is to besubstituted with a different amino acid monomer.

2. Production by Recombinant DNA Technology (a) Preparation of GenesEncoding KPI Variants

In a preferred embodiment of the invention, KPI variants are produced byrecombinant DNA technology. This requires the preparation of genesencoding each KPI variant that is to be made. Suitable genes can beconstructed by oligonucleotide synthesis using commercially availableequipment, such as that provided by Milligen and Applied Biosystems,supra. The genes can be prepared by synthesizing the entire coding andnon-coding strands, followed by annealing the two strands.Alternatively, the genes can be prepared by ligation of smallersynthetic oligonucleotides by methods well known in the art. Genesencoding KPI variants are produced by varying the nucleotides introducedat any step of the synthesis to change the amino acid sequence encodedby the gene.

Preferably, however, KPI variants are made by site-directed mutagenesisof a gene encoding KPI. Methods of site-directed mutagenesis are wellknown in the art. See, for example, Ausubel et al., (eds.) CURRENTPROTOCOLS IN MOLECULAR BIOLOGY (Wiley Interscience, 1987); PROTEINENGINEERING (Oxender & Fox eds., A. Liss, Inc. 1987). These methodsrequire the availability of a gene encoding KPI or a variant thereof,which can then be mutagenized by known methods to produce the desiredKPI variants. In addition, linker-scanning and polymerase chain reaction("PCR") mediated techniques can be used for purposes of mutagenesis. SeePCR TECHNOLOGY (Erlich ed., Stockton Press 1989); CURRENT PROTOCOLS INMOLECULAR BIOLOGY, vols. 1 & 2, loc. cit.

A gene encoding KPI can be obtained by cloning the naturally occurringgene, as described for example in U.S. Pat. Nos. 5,223,482 and5,187,153, which are hereby incorporated by reference in theirentireties. In particular, see columns 6-9 of U.S. Pat. No. 5,187,153.See also PCT Application No. 93/09233. In a preferred embodiment of theinvention a synthetic gene encoding KPI is produced by chemicalsynthesis, as described above. The gene may encode the 57-amino acid KPIdomain shown in Table 1, or it may also encode additional N-terminalamino acids from the APPI protein sequence, such as the four amino acidsequence (SEQ ID NO:8) (Glu-Val-Val-Arg, designated residues -4 to -1)immediately preceding the KPI domain in APPI.

Production of the gene by synthesis allows the codon usage of the KPIgene to be altered to introduce convenient restriction endonucleaserecognition sites, without altering the sequence of the encoded peptide.In a preferred embodiment of the invention, the synthetic KPI genecontains restriction endonuclease recognition sites that facilitateexcision of DNA cassettes from the KPI gene. These cassettes can bereplaced with small synthetic oligonucleotides encoding the desiredchanges in the KPI peptide sequence. See Ausubel, supra.

This method also allows the production of genes encoding KPI as a fusionpeptide with one or more additional peptide or protein sequences. TheDNA encoding these additional sequences is arranged in-frame with thesequence encoding KPI such that, upon translation of the gene, a fusionprotein of KPI and the additional peptide or protein sequence isproduced. Methods of making such fusion proteins are well known in theart. Examples of additional peptide sequences that can be encoded in thegenes are secretory signal peptide sequences, such as bacterial leadersequences, for example ompA and phoA, that direct secretion of proteinsto the bacterial periplasmic space. In a preferred embodiment of theinvention, the additional peptide sequence is a yeast secretory signalsequence, such as α-mating factor, that directs secretion of the peptidewhen produced in yeast.

Additional genetic regulatory sequences can also be introduced into thesynthetic gene that are operably linked to the coding sequence of thegene, thereby allowing synthesis of the protein encoded by the gene whenthe gene is introduced into a host cell. Examples of regulatory geneticsequences that can be introduced are: promoter and enhancer sequencesand transcriptional and translational control sequences. Otherregulatory sequences are well known in the art. See Ausubel et al.,supra, and Sambrook et al., supra.

Sequences encoding other fusion proteins and genetic elements are wellknown to those of skill in the art. In a preferred embodiment of theinvention, the KPI sequence is prepared by ligating together syntheticoligonucleotides to produce a gene encoding an in-frame fusion proteinof yeast α-mating factor with either KPI (1→57) or KPI (-4→57).

The gene constructs prepared as described above are convenientlymanipulated in host cells using methods of manipulating recombinant DNAtechniques that are well known in the art. See, for example Sambrook etal., MOLECULAR CLONING: A LABORATORY MANUAL, Second Edition, (ColdSpring Harbor Laboratory Press, Cold Spring Harbor, N.Y. 1989), andAusubel, supra. In a preferred embodiment of the invention the host cellused for manipulating the KPI constructs is E. coli. For example, theconstruct can be ligated into a cloning vector and propagated in E. coliby methods that are well known in the art. Suitable cloning vectors aredescribed in Sambrook, supra, or are commercially available fromsuppliers such as Promega (Madison, Wis.), Stratagene (San Diego,Calif.) and Life Technologies (Gaithersburg, Md.).

Once a gene construct encoding KPI has been obtained, genes encoding KPIvariants are obtained by manipulating the coding sequence of theconstruct by standard methods of site-directed mutagenesis, such asexcision and replacement of small DNA cassettes, as described supra. SeeAusubel, supra, and Sinha et al., supra. See also U.S. Pat. No.5,373,090, which is herein incorporated by reference in its entirety.See particularly, columns 4-12 of U.S. Pat. No. 5,272,090. These genesare then used to produce the KPI variant peptides as described below.

Alternatively, KPI variants can be produced using phage display methods.See, for example, Dennis et al. supra, which is hereby incorporated byreference in its entirety. See also U.S. Pat. Nos. 5,223,409 and5,403,484, which are hereby also incorporated by reference in theirentireties. In these methods, libraries of genes encoding variants ofKPI are fused in-frame to genes encoding surface proteins of filamentousphage, and the resulting peptides are expressed (displayed) on thesurface of the phage. The phage are then screened for the ability tobind, under appropriate conditions, to serine proteases of interestimmobilized on a solid support. Large libraries of phage can be used,allowing simultaneous screening of the binding properties of a largenumber of KPI variants. Phage that have desirable binding properties areisolated and the sequences of the genes encoding the corresponding KPIvariants is determined. These genes are then used to produce the KPIvariant peptides as described below.

(b) Expression of KPI Variant Peptides

Once genes encoding KPI variants have been prepared, they are insertedinto an expression vector and used to produce the recombinant peptide.Suitable expression vectors and corresponding methods of expressingrecombinant proteins and peptides are well known in the art. Methods ofexpressing KPI peptides are described in U.S. Pat. No. 5,187,153,columns 9-11, U.S. Pat. No. 5,223,482, columns 9-11, and PCT application93/09233, pp. 49-67. See also Ausubel et al., supra, and Sambrook etal., supra. The gene can be expressed in any number of differentrecombinant DNA expression systems to generate large amounts of the KPIvariant, which can then be purified and tested for its ability to bindto and inhibit serine proteases of interest.

Examples of expression systems known to the skilled practitioner in theart include bacteria such as E. coli, yeast such as Saccharomycescerevisiae and Pichia pastoris, baculovirus, and mammalian expressionsystems such as in Cos or CHO cells. In a preferred embodiment, KPIvariants are expressed in S. cerevisiae. In another preferred embodimentthe KPI variants are cloned into expression vectors to produce achimeric gene encoding a fusion protein of the KPI variant with yeastα-mating factor. The mating factor acts as a signal sequence to directsecretion of the fusion protein from the yeast cell, and is then cleavedfrom the fusion protein by a membrane-bound protease during thesecretion process. The expression vector is transformed into S.cerevisiae, the transformed yeast cells are cultured by standardmethods, and the KPI variant is purified from the yeast growth medium.

Recombinant bacterial cells expressing the peptides of the presentinvention, for example, E. coli, are grown in any of a number ofsuitable media, for example LB, and the expression of the recombinantantigen induced by adding IPTG to the media or switching incubation to ahigher temperature. After culturing the bacteria for a further period ofbetween 2 and 24 hours, the cells are collected by centrifugation andwashed to remove residual media. The bacterial cells are then lysed, forexample, by disruption in a cell homogenizer and centrifuged to separatedense inclusion bodies and cell membranes from the soluble cellcomponents. This centrifugation can be performed under conditionswhereby dense inclusion bodies are selectively enriched by incorporationof sugars such as sucrose into the buffer and centrifugation at aselective speed. If the recombinant peptide is expressed in inclusionbodies, as is the case in many instances, these can be washed in any ofseveral solutions to assist in the removal of any contaminating hostproteins, then solubilized in solutions containing high concentrationsof urea (e.g., 8M) or chaotropic agents such as guanidine hydrochloridein the presence of reducing agents such as β-mercaptoethanol or DTT(dithiothreitol).

At this stage it may be advantageous to incubate the peptides of thepresent invention for several hours under conditions suitable for thepeptides to undergo a refolding process into a conformation which moreclosely resembles that of native KPI. Such conditions generally includelow protein concentrations less than 500 μg/ml, low levels of reducingagent, concentrations of urea less than 2M and often the presence ofreagents such as a mixture of reduced and oxidized glutathione whichfacilitate the interchange of disulphide bonds within the proteinmolecule. The refolding process can be monitored, for example, bySDS-PAGE or with antibodies which are specific for the native molecule(which can be obtained from animals vaccinated with the native moleculeisolated from parasites). Following refolding, the peptide can then bepurified further and separated from the refolding mixture bychromatography on any of several supports including ion exchange resins,gel permeation resins or on a variety of affinity columns.

Purification of KPI variants can be achieved by standard methods ofprotein purification, e.g., using various chromatographic methodsincluding high performance liquid chromatography and adsorptionchromatography. The purity and the quality of the peptides can beconfirmed by amino acid analyses, molecular weight determination,sequence determination and mass spectrometry. See, for example, PROTEINPURIFICATION METHODS--A PRACTICAL APPROACH, Harris et al., eds. (IRLPress, Oxford, 1989). In a preferred embodiment, the yeast cells areremoved from the growth medium by filtration or centrifugation, and theKPI variant is purified by affinity chromatography on a column oftrypsin-agarose, followed by reversed-phase HPLC.

C. Measurement of Protease Inhibitory Properties of KPI Variants

Once KPI variants have been purified, they are tested for their abilityto bind to and inhibit serine proteases of interest in vitro. Thepeptides of the present invention preferably exhibit a more potent andspecific inhibition of serine proteases of interest than known serineprotease inhibitors, such as the natural KPI peptide domain. Suchbinding and inhibition can be assayed for by determining the inhibitionconstants for the peptides of the present invention toward serineproteases of interest and comparing those constants with constantsdetermined for known serine protease inhibitors, e.g., the native KPIdomain, toward those proteases. Methods for determining inhibitionconstants of protease inhibitors are well known in the art. See Fersht,ENZYME STRUCTURE AND MECHANISM, 2nd ed., W.H. Freeman and Co., New York,(1985).

In a preferred embodiment the inhibition experiments are carried outusing a chromogenic synthetic protease substrate, as described, forexample, in Bender et al., J. Amer. Chem. Soc. 88:5890 (1966).Measurements taken by this method can be used to calculate inhibitionconstants (K_(i) values) of the peptides of the present invention towardserine proteases of interest. See Bieth in BAYER-SYMPOSIUM V "PROTEINASEINHIBITORS", Fritz et al., eds., pp. 463-69, Springer-Verlag, Berlin,Heidelberg, N.Y., (1974). KPI variants that exhibit potent and specificinhibition of one or more serine proteases of interest may subsequentlybe tested in vivo. In vitro testing, however, is not a prerequisite forin vivo studies of the peptides of the present invention.

D. Testing of KPI Variants in vivo

The peptides of the present invention may be tested, alone or incombination, for their therapeutic efficacy by various in vivomethodologies known to those skilled in the art, e.g., the ability ofKPI variants to reduce postoperative bleeding can be tested in standardanimal models. For example, cardiopulmonary bypass surgery can becarried out on animals such as pigs in the presence of KPI variants, orin control animals where the KPI variant is not used. The use of pigs asa model for studying the clinical effects associated with CPB haspreviously been described. See Redmond et al., Ann. Thorac. Surg. 56:474(1993).

The KPI variant is supplied to the animals in a pharmaceutical sterilevehicle by methods known in the art, for example by continuousintravenous infusion. Chest tubes can be used to collect shed blood fora defined period of time. The shed blood, together with the residualintrathoracic blood found after sacrifice of the animal can be used tocalculate hemoglobin (Hgb) loss. The postoperative blood and Hgb loss isthen compared between the test and control animals to determine theeffect of the KPI variants.

E. Therapeutic Use of KPI Variants

KPI variants of the present invention found to exhibit therapeuticefficacy (e.g., reduction of blood loss following surgery in animalmodels) may preferably be used and administered, alone or in combinationor as a fusion protein, in a manner analogous to that currently used foraprotinin or other known serine protease inhibitors. See Butler et al.,supra. Peptides of the present invention generally may be administeredin the manner that natural peptides are administered. A therapeuticallyeffective dose of the peptides of the present invention preferablyaffects the activity of the serine proteases of interest such that theclinical condition may be treated, ameliorated or prevented.Therapeutically effective dosages of the peptides of the presentinvention can be determined by those skilled in the art, e.g., throughin vivo or in vitro models. Generally, the peptides of the presentinvention may be administered in total amounts of approximately 0.01 toapproximately 500, specifically 0.1 to 100 mg/kg body weight, if desiredin the form of one or more administrations, to achieve therapeuticeffect. It may, however, be necessary to deviate from suchadministration amounts, in particular depending on the nature and bodyweight of the individual to be treated, the nature of the medicalcondition to be treated, the type of preparation and the administrationof the peptide, and the time interval over which such administrationoccurs. Thus, it may in some cases be sufficient to use less than theabove amount of the peptides of the present invention, while in othercases the above amount is preferably exceeded. The optimal dose requiredin each case and the type of administration of the peptides of thepresent invention can be determined by one skilled in the art in view ofthe circumstances surrounding such administration. Such peptides can beadministered by intravenous injections, in situ injections, localapplications, inhalation, oral administration using coated polymers,dermal patches or other appropriate means. Compositions comprisingpeptides of the present invention are advantageously administered in theform of injectable compositions. Such peptides may be preferablyadministered to patients via continuous intravenous infusion, but canalso be administered by single or multiple injections. A typicalcomposition for such purpose comprises a pharmaceutically acceptablecarrier. Pharmaceutically acceptable carriers include aqueous solutions,non-toxic excipients, including salts, preservatives, buffers and thelike, as described in REMINGTON'S PHARMACEUTICAL SCIENCES, pp. 1405-12and 1461-87 (1975) and THE NATIONAL FORMULARY XIV., 14th Ed. Washington:American Pharmaceutical Association (1975). Aqueous carriers includewater, alcoholic/aqueous solutions, saline solutions, parenteralvehicles such as sodium chloride, Ringer's dextrose, etc. Intravenousvehicles include fluid and nutrient replenishers. Preservatives includeantimicrobials, anti-oxidants, chelating agents and inert gases. The pHand exact concentration of the various components of the composition areadjusted according to routine skills in the art. See GOODMAN ANDGILMAN'S THE PHARMACOLOGICAL BASIS FOR THERAPEUTICS (7th ed.). Thepeptides of the present invention may be present in such pharmaceuticalpreparations in a concentration of approximately 0.1 to 99.5% by weight,specifically 0.5 to 95% by weight, relative to the total mixture. Suchpharmaceutical preparations may also comprise other pharmaceuticallyactive substances in addition to the peptides of the present invention.Other methods of delivering the peptides to patients will be readilyapparent to the skilled artisan.

Examples of mammalian serine proteases that may exhibit inhibition bythe peptides of the present invention include: kallikrein; chymotrypsinsA and B; trypsin; elastase; subtilisin; coagulants and procoagulants,particularly those in active form, including coagulation factors such asthrombin and factors VIIa, IXa, Xa, XIa, and XIIa; plasmin;proteinase-3; enterokinase; acrosin; cathepsin; urokinase; and tissueplasminogen activator. Examples of conditions associated with increasedserine protease activity include: CPB-induced inflammatory response;post-CPB pulmonary injury; pancreatitis; allergy-induced proteaserelease; deep vein thrombosis; thrombocytopenia; rheumatoid arthritis;adult respiratory distress syndrome; chronic inflammatory bowel disease;psoriasis; hyperfibrinolytic hemorrhage; organ preservation; woundhealing; and myocardial infarction. Other examples of the use of thepeptides of the present invention are described in U.S. Pat. No.5,187,153.

The inhibitors of the present invention may also be used for inhibitionof serine protease activity in vitro, for example during the preparationof cellular extracts to prevent degradation of cellular proteins. Forthis purpose the inhibitors of the present invention may preferably beused in a manner analogous to the way that aprotinin, or other knownserine protease inhibitors, are used. The use of aprotinin as a proteaseinhibitor for preparation of cellular extracts is well known in the art,and aprotinin is sold commercially for this purpose.

The present invention, thus generally described, will be understood morereadily by reference to the following examples, which are provided byway of illustration and are not intended to be limiting of the presentinvention.

EXAMPLES Example 1 Expression of Wild-type KPI (-4→57)

A. Construction of PTW10:KPI

Plasmid PTW10:KPI is a bacterial expression vector encoding the 57 aminoacid form of KPI fused to the bacterial phoA signal sequence. Thestrategy for the construction of PTW10:KPI is shown in FIG. 1.

Plasmid pcDNAII (Invitrogen, San Diego, Calif.) was digested with PvuIIand the larger of the two resulting PvuII fragments (3013 bp) wasisolated. Bacterial expression plasmid pSP26 was digested with MluI andRsrII, and the 409 bp MluI-RsrII fragment containing the pTrp promoterelement and transcription termination signals was isolated byelectrophoresis in a 3% NuSieve Agarose gel (FMC Corp., Rockland,Mass.). Plasmid pSP26, containing a heparin-binding EGF-like growthfactor (HB-EGF) insert between the NdeI and HindIII sites, is describedas pNA28 in Thompson et al., J. Biol. Chem. 269:2541 (1994). PlasmidpSP26 was deposited in host E. coli W3110, pSP26 with the American TypeCulture Collection (ATCC), 12301 Parklawn Drive, Rockville, Md., 20852,USA under the conditions specified by the Budapest Treaty on theInternational Recognition of the Deposit of Microorganisms (BudapestTreaty). Host E. coli W3110, pSP26 was deposited on May 3, 1995 andgiven Accession No. 69800. Availability of the deposited plasmid is notto be construed as a license to practice the invention in contraventionof the rights granted under the authority of any government inaccordance with its patent laws.

The ends of the MluI-RsrII fragment were blunted using DNA polymeraseKlenow fragment by standard techniques. The blunted fragment of pSP26was then ligated into the large PvuII fragment of plasmid pCDNAII, andthe ligation mixture was used to transform E. coli strain MC1061.Ampicillin-resistant colonies were selected and used to isolate plasmidpTW10 by standard techniques.

A synthetic gene was constructed encoding the bacterial phoA secretorysignal sequence fused to the amino terminus of KPI(1→57). The syntheticgene contains cohesive ends for NdeI and HindIII, and also incorporatesrestriction endonuclease recognition sites for AgeI, RsrII, AatII andBamHI, as shown in FIG. 2. The synthetic phoA-KPI gene was constructedfrom 6 oligonucleotides of the following sequences (shown 5'→3'):

6167(SEQ ID NO:9): TATGAAACAAAGCACTATTGCACTGGCACTCTTACCGTTACTGTTTACCCCTGTGACAAAAGCCGAGGTGTGCTCTGAA

6169(SEQ ID NO:10): CTCGGCTTTTGTCACAGGGGTAAACAGTAACGGTAAGAGTGCCAGTGCAATAGTGCTTTGTTTCATA

6165(SEQ ID NO:11): CAAGCTGAGACCGGTCCGTGCCGTGCAATGATCTCCCGCTGGTACTTTGACGTCACTGAAGGTAAGTGCGCTCCATTCTTT

6166(SEQ ID NO:12): GCACTTACCTTCAGTGACGTCAAAGTACCAGCGGGAGATCATTGCACGGCACGGACCGGTCTCAGCTTGTTCAGAGCACAC

6168(SEQ ID NO:13): TACGGCGGTTGCGGCGGCAACCGTAACAACTTTGACACTGAAGAGTACTGCATGGCAGTGTGCGGATCCGCTATTTAAGCT

6164(SEQ ID NO:14): AGCTTAAATAGCGGATCCGCACACTGCCATGCAGTACTCTTCAGTGTCAAAGTTGTTACGGTTGCCGCCGCAACCGCCGTAAAAGAATGGAGC

The oligonucleotides were phosphorylated and annealed in pairs:6167+6169, 6165+6166, 6168 +6164. In 20 μl T4 DNA Ligase Buffer (NewEngland Biolabs, Beverley, Mass.), 1 μg of each oligonucleotide pair wasincubated with 10 U T4 Polynucleotide Kinase (New England Biolabs) for 1h at 37° C., then heated to 95° C. for 1 minute, and slow-cooled to roomtemperature to allow annealing. All three annealed oligo pairs were thenmixed for ligation to one another in a total volume of 100 μl T4 DNALigase Buffer, and incubated with 400 U T4 DNA Ligase (New EnglandBiolabs) overnight at 15° C. The ligation mixture was extracted with anequal volume of phenol:CHCl₃ (1:1), ethanol-precipitated, resuspended in50 μl Restriction Endonuclease Buffer #4 (New England Biolabs) anddigested with NdeI and HindIII. The annealed, ligated and digestedoligos were then subjected to electrophoresis in a 3% NuSieve Agarosegel, and the 240 bp NdeI-HindIII fragment was excised. This gel-purifiedsynthetic gene was ligated into plasmid pTW10 which had previously beendigested with NdeI and HindIII, and the ligation mixture was used totransform E. coli strain MC1061. Ampicillin-resistant colonies wereselected and used to prepare plasmid pTW10:KPI. This plasmid containsthe phoA-KPI(1→57) fusion protein inserted between the pTrp promoterelement and the transcription termination signals.

B. Construction of pKPI-61

The strategy for constructing pKPI-61 is shown in FIG. 3. PlasmidpTW10:KPI was digested with AgeI and HindIII; the resulting 152 bpAgeI-HindIII fragment containing a portion of the KPI synthetic gene wasisolated by preparative gel electrophoresis. An oligonucleotide pair(129+130) encoding the 9 amino-terminal residues of KPI(1→57) and 4amino acids of yeast α-mating factor was phosphorylated and annealed asdescribed above.

129(SEQ ID NO:15): CTAGATAAAAGAGAGGTGTGCTCTGAACAAGCTGAGA

130(SEQ ID NO: 16): CCGGTCTCAGCTTGTTCAGAGCACACCTCTCTTTTAT

The annealed oligonucleotides were then ligated to the AgeI-HindIIIfragment of the KPI (1→57) synthetic gene. The resulting 192 bpXbaI-HindIII synthetic gene (shown in FIG. 4) was purified bypreparative gel electrophoresis, and ligated into plasmid pUC19 whichhad previously been digested with XbaI and HindIII. The ligationproducts were used to transform E. coli strain MC1061.Ampicillin-resistant colonies were picked and used to prepare plasmidPKPI-57 by standard methods. To create a synthetic gene encodingKPI(-4→57), PKPI-57 was digested with XbaI and AgeI and the smallerfragment replaced with annealed oligos 234+235, which encode 4 aminoacid residues of yeast α-mating factor fused a 4 amino acid residueamino-terminal extension of KPI (1→57).

234(SEQ ID NO:17): CTAGATAAAAGAGAGGTTGTTAGAGAGGTGTGCTCTGAACAAGCTGAGA

235(SEQ ID NO:18): CCGGTCTCAGCTTGTTCAGAGCACACCTCTCTAACAACCTCTCTTTTAT

The 4 extra amino acids are encoded in the amyloid β-proteinprecursor/protease nexin-2 (APPI) which contains the KPI domain. Thesynthetic 201 bp XbaI-HindIII fragment encoding KPI(-4→57) in pKPI-61 isshown in FIG. 5.

C. Assembly of pTW113

The strategy for the construction of PTW113 is shown in FIG. 6. PlasmidpSP35 was constructed from yeast expression plasmid pYES2 (Invitrogen,San Diego, Calif.) as follows. A 267 bp PvuII-XbaI fragment wasgenerated by PCR from yeast α-mating factor DNA using oligos 6274 and6273:

6274(SEQ ID NO:19): GGGGGCAGCTGTATAAACGATTAAAA

6273(SEQ ID NO:20): GGGGGTCTAGAGATACCCCTTCTTCTTTAG

This PCR fragment, encoding an 82 amino acid portion of yeast α-matingfactor, including the secretory signal peptide and pro-region, wasinserted into pYES2 that had been previously digested with PvuII andXbaI. The resulting plasmid is denoted pSP34.

Two oligonucleotide pairs, 6294+6292 were then ligated to 6290+6291, andthe resulting 135 bp fragment was purified by gel electrophoresis.

6294(SEQ ID NO:21): CTAGATAAAAGAGAGGCTGAGGCTCACGCTGAAGGTACTTTCACTTC

6290(SEQ ID NO:22): TGACGTCTCTTCTTACTTGGAAGGTCAAGCTGCTAAGGAATTCATCGCTTGGTTGGTCAAAGGTAGAGGTTAAGCTTA

6291(SEQ ID NO:23): CTAGTAAGCTTAACCTCTACCTTTGACCAACCAAGCGATGAATTCCTTAGCA

6292(SEQ ID NO:24): GCTTGACCTTCCAAGTAAGAAGAGACGTCAGAAGTGAAAGTACCTTCAGCGTGAGCCTCAGCCTCTCTTTTAT

The resulting synthetic fragment was ligated into the XbaI site ofpSP34, resulting in plasmid pSP35. pSP35 was digested with XbaI andHindIII to remove the insert, and ligated with the 201 bp XbaI-HindIIIfragment of pKPI-61, encoding KPI(-4→57). The resulting plasmid pTW113,encodes the 445 bp synthetic gene for the α-factor-KPI(-4→57) fusion.See FIG. 7.

D. Transformation of Yeast with pTW113

Saccharomyces cerevisiae strain ABL115 was transformed with plasmidpTW113 by electroporation by the method of Becker et al., MethodsEnzymol. 194:182 (1991). An overnight culture of yeast strain ABL115 wasused to inoculate 200 ml YPD medium. The inoculated culture was grownwith vigorous shaking at 30° C. to an OD₆₀₀ of 1.3-1.5, at which timethe cells were harvested by centrifugation at 5000 rpm for 5 minutes.The cell pellet was resuspended in 200 ml ice-cold water, respun,resuspended in 100 ml ice-cold water, then pelleted again. The washedcell pellet was resuspended in 10 ml ice-cold 1M sorbitol,recentrifuged, then resuspended in a final volume of 0.2 ml ice-cold 1Msorbitol. A 40 μl aliquot of cells was placed into the chamber of a cold0.2 cm electroporation cuvette (Invitrogen), along with 100 ng plasmidDNA for pTW113. The cuvette was placed into an Invitrogen ElectroporatorII and pulsed at 1500 V, 25 μF, 100Ω. Electroporated cells were dilutedwith 0.5 ml 1M sorbitol, and 0.25 ml was spread on an SD agar platecontaining 1M sorbitol. After 3 days' growth at 30° C., individualcolonies were streaked on SD+CAA agar plates.

E. Induction of pTW113/ABL115, Purification of KPI(-4→57)

Yeast cultures were grown in a rich broth and the galactose promoter ofthe KPI expression vector induced with the addition of galactose asdescribed by Sherman, Methods Enzymol. 194:3 (1991). A singlewell-isolated colony of pTW113/ABL115 was used to inoculate a 10 mlovernight culture in Yeast Batch Medium. The next day, 1L Yeast BatchMedium which had been made 0.2% glucose was inoculated to an OD₆₀₀ of0.1 with the overnight culture. Following 24 hours at 30° C. withvigorous shaking, the 1L culture was induced by the addition of 20 mlYeast Galactose Feed Medium. Following induction, the culture was fedevery 12 hours with the addition of 20 ml Yeast Galactose Feed Medium.At 48 hours after induction, the yeast broth was harvested bycentrifugation, then adjusted to pH 7.0 with 2M Tris, pH 10. The brothwas subjected to trypsin-Sepharose affinity chromatography, and boundKPI(-4→57) was eluted with 20 mM Tris pH 2.5. See Schilling et al., Gene98:225 (1991). Final purification of KPI(-4→57) was accomplished by HPLCchromatography on a semi-prep Vydac C4 column in a gradient of 20% to35% acetonitrile. The sample was dried and resuspended in PBS at 1-2mg/ml. The amino acid sequence of KPI(-4→57) is shown in FIG. 8.

Example 2 Recombinant Expression of Site-directed KPI(-4→57) Variants

Expression vectors for the production of specific variants of KPI(-4→57)were all constructed using the pTW113 backbone as a starting point. Foreach KPI variant, an expression construct was created by replacing the40 bp RsrII-AatII fragment of the synthetic KPI gene contained in pTW113with a pair of annealed oligonucleotides which encode specific codonsmutated from the wild-type KPI(-4→57) sequence. In the followingExamples the convention used for designating the amino substituents inthe KPI variants indicates first the single letter code for the aminoacid found in wild-type KPI, followed by the position of the residueusing the numbering convention described supra, followed by the code forthe replacement amino acid. Thus, for example, M15R indicates that themethionine residue at position 15 is replaced by an arginine.

A. Construction of pTW6165

The strategy for constructing pTW6165 is shown in FIG. 9. Plasmid pTW113was digested with RsrII and AatII, and the larger of the two resultingfragments was isolated. An oligonucleotide pair (812+813) wasphosphorylated, annealed and gel-purified as described above.

812(SEQ ID NO:25): GTCCGTGCCGTGCAGCTATCTGGCGCTGGTACTTTGACGT

813(SEQ ID NO:26): CAAAGTACCAGCGCCAGATAGCTGCACGGCACG

The annealed oligonucleotides were ligated into the RsrII andAatII-digested pTW113, and the ligation product was used to transform E.coli strain MC1061. Transformed colonies were selected by ampicillinresistance. The resulting plasmid, pTW6165, encodes the 445 bp syntheticgene for the α-factor-KPI(-4→57; M15A, S17W) fusion. See FIG. 10.

B. Construction of pTW6166, pTW6175, pBG028, pTW6183, pTW6184, pTW6185,pTW6173, pTW6174.

Construction of the following KPI(-4→57) variants was accomplishedexactly as outlined for pTW6165. The oligonucleotides utilized for eachconstruct are denoted below, and the sequences of annealedoligonucleotide pairs are shown in FIG. 11. FIGS. 12-19 show thesynthetic genes for the α-factor fusions with each KPI(-4→57) variant.

pTW6166; KPI(-4→57; M15A, S17Y)--See FIG. 12

814(SEQ ID NO:27): GTCCGTGCCGTGCAGCTATCTACCGCTGGTACTTTGACGT

815(SEQ ID NO:28): CAAAGTACCAGCGGTAGATAGCTGCACGGCACG

pTW6175: KPI(-4→57; M15L, S17F)--See FIG. 13

867(SEQ ID NO:29): GTCCGTGCCGTGCATTGATCTTCCGCTGGTACTTTGACGT

868(SEQ ID NO:30): CAAAGTACCAGCGGAAGATCAATGCACGGCACG

pBG028: KPI(-4→57; M15L, S17Y)--See FIG. 14

1493(SEQ ID NO:31): GTCCGTGCCGTGCTTTGATCTACCGCTGGTACTTTGACGT

1494(SEQ ID NO:32): CAAAGTACCAGCGGTAGATCAAAGCACGGCACG

pTW6183: KPI(-4→57; I16H, S17F)--See FIG. 15

925(SEQ ID NO:33): GTCCGTGCCGTGCAATGCACTTCCGCTGGTACTTTGACGT

926(SEQ ID NO:34): CAAAGTACCAGCGGAAGTGCATTGCACGGCACG

pTW6184: KPI(-4→57; I16H, S17Y)--See FIG. 16

927(SEQ ID NO:35): GTCCGTGCCGTGCAATGCACTACCGCTGGTACTTTGACGT

928(SEQ ID NO:36): CAAAGTACCAGCGGTAGTGCATTGCACGGCACG

pTW6185: KPI(-4→57; I16H, S17W)--See FIG. 17

929(SEQ ID NO:37): GTCCGTGCCGTGCAATGCACTGGCGCTGGTACTTTGACGT

930(SEQ ID NO:38): CAAAGTACCAGCGCCAGTGCATTGCACGGCACG

pTW6173: KPI(-4→57; M15A, I16H)--See FIG. 18

863(SEQ ID NO:39): GTCCGTGCCGTGCAGCTCACTCCCGCTGGTACTTTGACGT

864(SEQ ID NO:40): CAAAGTACCAGCGGGAGTGAGCTGCACGGCACG

pTW6174: KPI(-4→57; M15L, I16H)--See FIG. 19

865(SEQ ID NO:41): GTCCGTGCCGTGCATTGCACTCCCGCTGGTACTTTGACGT

866(SEQ ID NO:42): CAAAGTACCAGCGGGAGTGCAATGCACGGCACG

C. Transformation of Yeast with Expression Vectors

Yeast strain ABL115 was transformed by electroporation exactly accordingto the protocol described for transformation by pTW113.

D. Induction of Transformed Yeast Strains, Purification of KPI(-4→57)Variants.

Cultures of yeast strains were grown and induced, and recombinantsecreted KPI(-4→57) variants were purified according to the proceduredescribed for KPI(-4→57). The amino acid sequences of KPI(-4→57)variants are shown in FIGS. 20-29.

Example 3 Identification of KPI (-4→57; M15A, S17F) DD185 by PhageDisplay

A. Construction of vector pSP26:Amp:F1

The construction of pSP26; Amp:F1 is outlined in FIG. 30. VectorpSP26:Amp:F1 contributes the basic plasmid backbone for the constructionof the phage display vector for the phoA:KPI fusion, PDW1 #14.pSP26:Amp:F1 contains a low-copy number origin of replication, theampicillin-resistance gene (Amp) and the F1 origin for production ofsingle-stranded phagemid DNA.

The ampicillin-resistance gene (Amp) was generated through polymerasechain reaction (PCR) amplification from the plasmid genome of PUC19using oligonucleotides 176 and 177.

176(SEQ ID NO:43): GCCATCGATGGTTTCTTAAGCGTCAGGTGGCACTTTTC

177(SEQ ID NO:44): GCGCCAATTCTTGGTCTACGGGGTCTGACGCTCAGTGGAACGAA

The PCR amplification of Amp was done according to standard techniques,using Taq polymerase (Perkin-Elmer Cetus, Norwalk, Conn.). Amplificationfrom plasmid pUC19 with these oligonucleotides yielded a fragment of1159 bp, containing PflMI and ClaI restriction sites. The PCR productwas digested with PflMI and ClaI and purified by agarose gelelectrophoresis in 3% NuSieve Agarose (FMC Corp.). Bacterial expressionvector pSP26 (supra) was digested with PflMI and ClaI and the largervector fragment was purified. The PflMI-ClaI PCR fragment was ligatedinto the previously digested pSP26 containing the Amp gene. The ligationproduct was used to transform E. coli strain MC1061 and colonies wereselected by ampicillin resistance. The resulting plasmid is denotedpSP26:Amp.

The F1 origin of replication from the mammalian expression vectorpcDNAII (Invitrogen) was isolated in a 692 bp EarI fragment. PlasmidpcDNAII was digested with EarI and the resulting 692 bp fragmentpurified by agarose gel electrophoresis. EarI-NotI adapters were addedto the 692 bp EarI fragment by ligation of two annealed oligonucleotidepairs, 179+180 and 181+182. The oligo pairs were annealed as describedabove.

179(SEQ ID NO:45): GGCCGCTCTTCC

180(SEQ ID NO:46): AAAGGAAGAGC

181(SEQ ID NO:47): CTAGAATTGC

182(SEQ ID NO:48): GGCCGCAATTC

The oligonucleotide-ligated fragment was then ligated into the singleNotI site of PSP26:Amp to yield the vector pSP26:Amp:F1.

B. Construction of Vector pgIII

The construction of pgIII is outlined in FIG. 31. The portion of thephage geneIII protein gene contained by the PDW1 #14 phagemid vector wasoriginally obtained as a PCR amplification product from vector m13mp8. Aportion of m13mp8 geneIII encoding the carboxyl-terminal 158 amino acidresidues of the geneIII product was isolated by PCR amplification ofm13mp8 nucleotide residues 2307-2781 using PCR oligos 6162 and 6160.

6162(SEQ ID NO:49): GCCGGATCCGCTATTTCCGGTGGTGGCTCTGGTTCC

6160(SEQ ID NO:50): GCCAAGCTTATTAAGACTCCTTATTACGCAG

The PCR oligos contain BamHI and HindIII restriction recognition sitessuch that PCR from m13mp8 plasmid DNA with the oligo pair yielded a 490bp BamHI-HindIII fragment encoding the appropriate portion of geneIII.The PCR product was ligated between the BamHI and HindIII sites withinthe polylinker of PUC19 to yield plasmid pgIII.

C. Construction of pPhoA:KPI:gIII

Construction of pPhoA:KPI:gIII is outlined in FIG. 32. A portion of thephoA signal sequence and KPI fusion encoded by the phage display vectorPDW1 #14 originates with pPhoA:KPI:gIII. The 237 bp NdeI-HindIIIfragment of pTW10:KPI encoding the entire phoA:KPI (1→57) fusion wasisolated by preparative agarose gel electrophoresis, and insertedbetween the NdeI and HindIII sites of pUC19 to yield plasmid pPhoA:KPI.The 490 bp BamHI-HindIII fragment of pgIII encoding the C-terminalportion of the geneIII product was then isolated and ligated between theBamHI and HindIII sites of pPhoA:KPI to yield vector pPhoa:KPI:gIII. ThepPhoA:KPI:gIII vector encodes a 236 amino acid residue fusion of thephoA signal peptide, KPI (1→57) and the carboxyl-terminal portion of thegeneIII product.

D. Construction of pLG1

Construction of pLG1 is illustrated in FIG. 33. The exact geneIIIsequences contained in vector PDW1 #14 originate with phage displayvector pLG1. A modified geneIII segment was generated by PCRamplification of the geneIII region from pgIII using PCRoligonucleotides 6308 and 6305.

6308(SEQ ID NO:51): AGCTCCGATCTAGGATCCGGTGGTGGCTCTGGTTCCGGT

6305(SEQ ID NO:52): GCAGCGGCCGTTAAGCTTATTAAGACTCCT

PCR amplification from pgIII with these oligonucleotides yielded a 481bp BamHI-HindIII fragment encoding a geneIII product shortened by 3amino acid residues at the amino-terminal portion of the segment of thegeneIII fragment encoded by pgIII. A 161 bp NdeI-BamHI fragment wasgenerated by PCR amplification from bacterial expression plasmid pTHW05using oligonucleotides 6306 and 6307.

6306(SEQ ID NO:53): GATCCTTGTGTCCATATGAAACAAAGC

6307(SEQ ID NO:54): CACGTCGGTCGAGGATCCCTAACCACGGCCTTTAACCAG

The 161 bp NdeI-BamHI fragment and the 481 bp BamHI-HindIII fragmentwere gel-purified, and then ligated in a three-way ligation into PTW10which had previously been digested with NdeI and HindIII. The resultingplasmid pLG1 encodes a phoA signal peptide-insert-geneIII fusion forphage display purposes.

E. Construction of pAL51

Construction of pAL51 is illustrated in FIG. 34. Vector pAL51 containsthe geneIII sequences of pLG1 which are to be incorporated in vectorpDW1 #14.

A 1693 bp fragment of plasmid pBR322 was isolated, extending from theBamHI site at nucleotide 375 to the PvuII site at position 2064. PlasmidpLG1 was digested with Asp718I and BamHI, removing an 87 bp fragment.The overhanging Asp718I end was blunted by treatment with Klenowfragment, and the PvuII-BamHI fragment isolated from pBR322 was ligatedinto this vector, resulting in the insertion of a 1693 bp "stuffer"region between the Asp718I and BamHI sites. The 78 bp NdeI-Asp718Iregion of the resulting plasmid was removed and replaced with theannealed oligo pair 6512+6513.

6512(SEQ ID NO:55): TATGAAACAAAGCACTATTGCACTGGCACTCTTACCGTTACTGTTTACCCCGGTGACCAAAGCCCACGCTGAAG

6513(SEQ ID NO:56): GTACCTTCAGCGTGGGCTTTGGTCACCGGGGTAAACAGTAACGGTAAGAGTGCCAGTGCAATAGTGCTTTGTTTCA

The newly created 74 bp NdeI-Asp718I fragment encodes the phoA signalpeptide, and contains a BstEII cloning site. The resulting plasmid isdenoted pAL51.

F. Construction of pAL53

Construction of pAL53 is outlined in FIG. 35. Plasmid pAL53 contributesmost of the vector sequence of pDW1 #14, including the basic vectorbackbone with Amp gene, F1 origin, low copy number origin ofreplication, geneIII segment, phoA promotor and phoA signal sequence.

Plasmid pAL51 was digested with NdeI and HindIII and the resulting 2248bp NdeI-HindIII fragment encoding the phoA signal peptide, stufferregion and geneIII region was isolated by preparative agarose gelelectrophoresis. The NdeI-HindIII fragment was ligated into plasmidpSP26:Amp:F1 between the NdeI and HindIII sites, resulting in plasmidpAL52.

The phoA promoter region and signal peptide was generated byamplification of a portion of the E. coli genome by PCR, usingoligonucleotide primers 405 and 406.

405(SEQ ID NO:57): CCGGACGCGTGGAGATTATCGTCACTG

406(SEQ ID NO:58): GCTTTGGTCACCGGGGTAAACAGTAACGG

The resulting PCR product is a 332 bp MluI-BstEII fragment whichcontains the phoA promoter region and signal peptide sequence. Thisfragment was used to replace the 148 bp MluI-BstEII segment of PAL52,resulting in vector pAL53.

G. Construction of pSP26:Amp:F1:PhoA:KPI:gIII

Construction of pSP26:Amp:F1:PhoA:KPI:gIII is illustrated in FIG. 36.This particular vector is the source of the KPI coding sequence found invector pDW1 #14. Plasmid pPhoa:KPI:gIII was digested with NdeI andHindIII, and the resulting 714 bp NdeI-HindIII fragment was purified,and then inserted into vector pSP26:Amp:F1 between the NdeI and HindIIIsites. The resulting plasmid is denoted pSP26:Amp:F1:PhoA:KPI:gIII.

H. Construction of PDW1 #14

Construction of pDW1 #14 is illustrated in FIG. 37. The sequencesencoding KPI were amplified from plasmid pSP26:Amp:F1:PhoA:KPI:gIII byPCR, using oligonucleotide primers 424 and 425.

424(SEQ ID NO:59): CTGTTTACCCCGGTGACCAAAGCCGAGGTGTGCTCTGAACAA

425(SEQ ID NO:60): AATAGCGGATCCGCACACTGCCATGCAGTACTCTTC

The resulting 172 bp BstEII-BamHI fragment encodes most of KPI (1→55).This fragment was used to replace the stuffer region in pAL53 betweenthe BstEII and BamHI sites. The resulting plasmid, PDW1 #14, is theparent KPI phage display vector for preparation of randomized KPI phagelibraries. The coding region for the phoA-KPI (1→55)-geneIII fusion isshown in FIG. 38.

I. Construction of pDW1 14-2

Construction of pDW1 14-2 is illustrated in FIG. 39. The first step inthe construction of the KPI phage libraries in pDW1 #14 was thereplacement of the AgeI-BamHI fragment within the KPI coding sequencewith a stuffer fragment. This greatly aids in preparation of randomizedKPI libraries which are substantially free of contamination of phagemidgenomes encoding wild-type KPI sequence.

Plasmid pDW1 #14 was digested with AgeI and BamHI, and the 135 bpAgeI-BamHI fragment encoding KPI was discarded. A stuffer fragment wascreated by PCR amplification of a portion of the PBR322 Tet gene,extending from the BamHI site at nucleotide 375 to nucleotide 1284,using oligo primers 266 and 252.

266(SEQ ID NO:61): GCTTTAAACCGGTAGGTGGCCCGGCTCCATGCACC

252(SEQ ID NO:62): CGAATTCACCGGTGTCATCCTCGGCACCGTCACCCT

The resulting 894 bp AgeI-BamHI stuffer fragment was then inserted intothe AgeI/BamHI-digested pDW1 #14 to yield the phagemid vector pDW1 14-2.This vector was the starting point for construction of the randomizedKPI libraries.

J. Construction of KPI Library 16-19

Construction of KPI Library 16-19 is outlined in FIG. 40. Library 16-19was constructed to display KPI-geneIII fusions in which amino acidpositions Ala¹⁴, Met¹⁵, Ile¹⁶ and Ser¹⁷ are randomized. For preparationof the library, plasmid pDW1 14-2 was digested with AgeI and BamHI toremove the stuffer region, and the resulting vector was purified bypreparative agarose gel electrophoresis. Plasmid pDW1 #14 was used astemplate in a PCR amplification of the KPI region extending from theAgeI site to the BamHI site. The oligonucleotide primers used were 544and 551.

544(SEQ ID NO:63): GGGCTGAGACCGGTCCGTGCCGT(NNS)₄ CGCTGGTACTTTGACGTC

551(SEQ ID NO:64): GGAATAGCGGATCCGCACACTGCCATGCAG

Oligonucleotide primer 544 contains four randomized codons of thesequence NNS, where N represents equal mixtures of A/G/C/T and S anequal mixture of G or C. Each NNS codon thus encodes all 20 amino acidsplus a single possible stop codon, in 32 different DNA sequences. PCRamplification from the wild-type KPI gene resulted in the production ofa mixture of 135 bp AgeI-BamHI fragments all containing differentsequences in the randomized region. The PCR product was purified bypreparative agarose gel electrophoresis and ligated into the AgeI/BamHIdigested PDW1 14-2 vector. The ligation mixture was used to transform E.coli Top10F¹ cells (Invitrogen) by electroporation according to themanufacturer's directions. The resulting Library 16-19 containedapproximately 400,000 independent clones. The potential size of thelibrary, based upon the degeneracy of the priming PCR oligo #544 was1,048,576 members. The expression unit encoded by the members of Library16-19 is shown in FIG. 41.

K. Selection of Library 16-19 with Human Plasma Kallikrein

KPI phage were prepared and amplified by infecting transformed cellswith M13KO7 helper phage as described by Matthews et al., Science260:1113 (1993). Human plasma kallikrein (Enzyme Research Laboratories,South Bend, Ind.), was coupled to Sepharose 6B resin. Prior to phagebinding, the immobilized kallikrein resin was washed three times with0.5 ml assay buffer (AB=100 mM Tris-HCl, pH 7.5, 0.5M NaCl, 5 mM each ofKCl, CaCl₂, MgCl₂, 0.1% gelatin, and 0.05% Triton X-100). Approximately5×10⁹ phage particles of the amplified Library 16-19 in PBS, pH 7.5,containing 300 mM NaCl and 0.1% gelatin, were bound to 50 μl kallikreinresin containing 15 pmoles of active human plasma kallikrein in a totalvolume of 250 μl. Phage were allowed to bind for 4 h at roomtemperature, with rocking. Unbound phage were removed by washing thekallikrein resin three times in 0.5 ml AB. Bound phage were elutedsequentially by successive 5 minute washes: 0.5 ml 50 mM sodium citrate,pH 6.0, 150 mM NaCl; 0.5 ml 50 mM sodium citrate, pH 4.0, 150 mM NaCl;and 0.5 ml 50 mM glycine, pH 2.0, 150 mM NaCl. Eluted phage wereneutralized immediately and phagemids from the pH 2.0 elution weretitered and amplified for reselection. After three rounds of selectionon kallikrein-Sepharose, phagemid DNA was isolated from 22 individualcolonies and subjected to DNA sequence analysis.

The most frequently occurring randomized KPI region encoded(SEQ IDNO:65): Ala¹⁴ -Ala¹⁵ -Ile¹⁶ -Phe¹⁷. The phoA-KPI-geneIII region encodedby this class of selected KPI phage is shown in FIG. 42. The KPI variantencoded by these phagemids is denoted KPI (1→55; M15A, S17F).

L. Construction of pDD185 KPI (-4→57; M15A, S17F) FIG. 43 outlines theconstruction of pDD185 KPI (-4→57; M15A, S17F). The sequences encodingKPI (1→55; M15A, S17F) were moved from one phagemid vector, pDW1 (16-19)185, to the yeast expression vector so that the KPI variant could bepurified and tested.

Plasmid pTW113 encoding wild-type KPI (-4→57) was digested with AgeI andBamHI and the 135 bp AgeI-BamHI fragment was discarded. The 135 bpAgeI-BamHI fragment of pDW1 (16-19) 185 was isolated and ligated intothe yeast vector to yield plasmid pDD185, encoding α-factor fused to KPI(-4→57; M15A, S17F). See FIG. 44.

M. Purification of KPI (-4→57; M15A, S17F) pDD185

Transformation of yeast strain ABL115 with pDD185, induction of yeastcultures, and purification of KPI (-4→57; M15A, S17F) pDD185 wasaccomplished as described for the other KPI variants.

N. Construction of KPI Library 6--M15A, with Residues 14, 16-18 Random.

Library 6 was constructed to display KPI-geneIII fusions in which aminoacid positions Ala¹⁴, Ile¹⁶, Ser¹⁷ and Arg¹⁸ are randomized, butposition 15 was held constant as Ala. For preparation of the library,plasmid pDW1 #14 was used as template in a PCR amplification of the KPIregion extending from the AgeI site to the BamHI site. Theoligonucleotide primers used were 551 and 1003.

1003(SEQ ID NO:66): GCTGAGACCGGTCCGTGCCGTNNSGCA(NNS)₃ TGGTACTTTGACGTC

551(SEQ ID NO:64): GGAATAGCGGATCCGCACACTGCCATGCAG

Oligonucleotide primer 1003 contained four randomized codons of thesequence NNS, where N represents equal mixtures of A/G/C/T and S anequal mixture of G or C. Each NNS codon thus encodes all 20 amino acidsplus a single possible stop, in 32 different DNA sequences. PCRamplification from the wild-type KPI gene resulted in the production ofa mixture of 135 bp AgeI-BamHI fragments all containing differentsequences in the randomized region. The PCR product was phenolextracted, ethanol precipitated, digested with BamHI and purified bypreparative agarose gel electrophoresis. Plasmid pDW1 14-2 was digestedwith BamHI, phenol extracted and ethanol precipitated. The insert wasligated at high molar ratio to the vector which was then digested withAgeI to remove the stuffer region. The vector containing the insert waspurified by agarose gel electrophoresis and recircularized. Theresulting library contains approximately 5×10⁶ independent clones.

O. Construction of KPI Library 7--Residues 14-18 Random.

Library 7 was constructed to display KPI-geneIII fusions in which aminoacid positions Ala¹⁴, Met¹⁵, Ile¹⁶, Ser¹⁷ and Arg¹⁸ are randomized. Forpreparation of the library, plasmid pDW1 #14 was used as template in aPCR amplification of the KPI region extending from the AgeI site to theBamHI site. The oligonucleotide primers used were 551 and 1179.

1179(SEQ ID NO:67): GCTGAGACCGGTCCGTGCCGT(NNS)₅ TGGTACTTTGACGTC

551(SEQ ID NO:64): GGAATAGCGGATCCGCACACTGCCATGCAG

Oligonucleotide primer 1179 contains five randomized codons of thesequence NNS, where N represents equal mixtures of A/G/C/T and S anequal mixture of G or C. Each NNS codon thus encoded all 20 amino acidsplus a single possible stop, in 32 different DNA sequences. PCRamplification from the wild-type KPI gene resulted in the production ofa mixture of 135 bp AgeI-BamHI fragments all containing differentsequences in the randomized region. The PCR product was phenolextracted, ethanol precipitated, digested with BamHI and purified bypreparative agarose gel electrophoresis. Plasmid pDW1 14-2 was digestedwith BamHI, phenol extracted and ethanol precipitated. The insert wasligated at high molar ratio to the vector which was then digested withAgeI to remove the stuffer region. The vector containing the insert waspurified by agarose gel electrophoresis and recircularized. Theresulting library contains approximately 1×10⁷ independent clones.

P. Selection of Libraries 6 & 7 with Human Factor XIIa

KPI phage were prepared and amplified by infecting transformed cellswith M13K07 helper phage (Matthews and Wells, 1993). Human factor XIIa(Enzyme Research Laboratories, South Bend, Ind.), was biotinylated asfollows. Factor XIIa (0.5 mg) in 5 mM sodium acetate pH 8.3 wasincubated with Biotin Ester (Zymed) at room temperature for 1.5 h, thenbuffer-exchanged into assay buffer (AB). Approximately 1×10¹⁰ phageparticles of each amplified Library 6 or 7 in PBS, pH 7.5, containing300 mM NaCl and 0.1% gelatin, were incubated with 50 pmoles of activebiotinylated human factor XIIa in a total volume of 200 μl. Phage wereallowed to bind for 2 h at room temperature, with rocking. Following thebinding period, 100 μl Strepavidin Magnetic Particles (BoehringerMannheim) were added to the mixture and incubated at room temperaturefor 30 minutes. Separation of magnetic particles from the supernatantand wash/elution buffers was carried out using MPC-E-1Neodymium-iron-boron permanent magnets (Dynal). Unbound phage wereremoved by washing the magnetically bound biotinylated XIIa-phagecomplexes three times with 0.5 ml AB. Bound phage were elutedsequentially by successive 5 minute washes: 0.5 ml 50 mM sodium citrate,pH 6.0, 50 mM NaCl; 0.5 ml 50 mM sodium citrate, pH 4.0, 150 mM NaCl;and 0.5 ml 50 mM glycine, pH 2.0, 150 mM NaCl. Eluted phage wereneutralized immediately and phagemids from the pH 2.0 elution weretitered and amplified for reselection. After 3 or 4 rounds of selectionwith factor XIIa, phagemid DNA was isolated from individual colonies andsubjected to DNA sequence analysis.

Sequences in the randomized regions were compared with one another toidentify consensus sequences appearing more than once. From Library 6 aphagemid was identified which encoded M15L, S17Y, R18H. From Library 7 aphagemid was identified which encoded M15A, S17Y, R18H.

Q. Construction of pBG015 KPI (-4→57; M15L, S17Y, R18H), pBG022 (-4→57;M15A, S17Y, R18H)

The sequences encoding KPI (1→55; M15L, S17Y, R18H) and KPI (1→55; M17A,S17Y, R18H) were moved from the phagemid vectors to the yeast expressionvector so that the KPI variant could be purified and tested.

Plasmid pTW113 encoding wild-type KPI (-4→57) was digested with AgeI andBamHI and the 135 bp AgeI-BamHI fragment was discarded. The 135 bpAgeI-BamHI fragment of the phagemid vectors were isolated and ligatedinto the yeast vector to yield plasmids pBG015 and pBG022, encodingalpha-factor fused to KPI (-4→57; M15L, S17Y, R18H), and KPI (-4→57;M15A, S17Y, R18H), respectively.

R. Construction of pBG029 KPI (-4→57, T9V, M15L, S17Y, R18H)

Plasmid pBG015 was digested with XbaI and RsrII, and the larger of thetwo resulting fragments was isolated. An oligonucleotide pair(1593+1642) was phosphorylated, annealed and gel-purified as describedpreviously.

1593(SEQ ID NO:68): CTAGATAAAAGAGAGGTTGTTAGAGAGGTGTGCTCTGAACAAGCTGAGGTTG

1642(SEQ ID NO:69: GACCAACCTCAGCTTGTTCAGAGCACACCTCTCTAA CAACCTCTCTTTTAT

The annealed oligonucleotides were ligated into the XbaI andRsrII-digested pBG015, and the ligation product was used to transform E.coli strain MC1061 to ampicillin resistance. The resulting plasmidpBG029, encodes the 445 bp synthetic gene for the alpha-factor-KPI(-4→57; T9V, M15L, S17F, R18H) fusion.

S. Construction of pBG033 KPI (-4→57; T9V, M15A, S17Y, R18H)

Plasmid pBG022 was digested with XbaI and RsrII, and the larger of thetwo resulting fragments was isolated. An oligonucleotide pair(1593+1642) was phosphorylated, annealed and gel-purified as describedpreviously. The annealed oligonucleotides were ligated into the XbaI andRsrII-digested pBG022, and the ligation product was used to transform E.coli strain MC1061 to ampicillin resistance. The resulting plasmidpBG033, encodes the 445 bp synthetic gene for the alpha-factor-KPI(-4→57; T9V, M15A, S17F, R18H) fusion.

T. Selection of Library 16-19 with Human Factor Xa

KPI phage were prepared and amplified by infecting transformed cellswith M13K07 helper phage (Matthews and Wells, 1993). Human factor Xa(Haematologic Technologies, Inc., Essex Junction, Vt.) was coupled toSepharose 6B resin. Prior to phage binding, the immobilized Xa resin waswashed three times with 0.5 ml assay buffer (AB=100 mM Tris-HCl, pH 7.5,0.5M NaCl, 5 mM each of KCl, CaCl₂, MgCl₂, 0.1% gelatin, and 0.05%Triton X-100). Approximately 4×10¹⁰ phage particles of the amplifiedLibrary 16-19 in PBS, pH 7.5, containing 300 mM NaCl and 0.1% gelatin,were bound to 50 μl Xa resin in a total volume of 250 μl. Phage wereallowed to bind for 4 h at room temperature, with rocking. Unbound phagewere removed by washing the Xa resin three times in 0.5 ml AB. Boundphage were eluted sequentially by successive 5 minute washes: 0.5 ml 50mM sodium citrate, pH 6.0, 150 mM NaCl; 0.5 ml 50 mM sodium citrate, pH4.0 150 mM NaCl; and 0.5 ml 50 mM glycine, pH 2.0, 150 mM NaCl. Elutedphage were neutralized immediately and phagemids from the pH 2.0 elutionwere titered and amplified for reselection. After three rounds ofselection on Xa-Sepharose, phagemid DNA was isolated and subjected toDNA sequence analysis.

Sequences in the randomized Ala¹⁴ -Ser¹⁷ region were compared with oneanother to identify consensus sequences appearing more than once. Aphagemid was identified which encoded KPI (1→55; M15L, I16F, S17K).

U. Construction of pDD131 KPI (-4→57; M15L, I16F, S17K)

The sequences encoding KPI (1→55; M15L, I16F, S17K) were moved from thephagemid vector to the yeast expression vector so that the KPI variantcould be purified and tested.

Plasmid pTW113 encoding wild-type KPI (-4→57) was digested with AgeI andBamHI and the 135 bp AgeI-BamHI fragment was discarded. The 135 bpAgeI-BamHI fragment of the phagemid vector was isolated and ligated intothe yeast vector to yield plasmid pDD131, encoding alpha-factor fused toKPI (-4→57; M15L, I16F, S17K).

V. Construction of pDD134 KPI (-4→57; M15L, I16F, S17K, G37Y)

Plasmid pDD131 was digested with AatI and BamHI, and the larger of thetwo resulting fragments was isolated. An oligonucleotide pair (738+739)was phosphorylated, annealed and gel-purified as described previously.

738(SEQ ID NO:70): CACTGAAGGTAAGTGCGCTCCATTCTTTTACGGCGGTTGCTACGGCAACCGTAACAACTTTGACACTGAAGAGTACTGCATGGCAGTGTGCG

739(SEQ ID NO:71): GATCCGCACACTGCCATGCAGTACTCTTCAGTGTCAAAGTTGTTACGGTTGCCGTAGCAACCGCCGTAAAAGAATGGAGCGCACTTACCTTCAGTGACGT

The annealed oligonucleotides were ligated into the AatI andBamHI-digested pDD131, and the ligation product was used to transform E.coli strain MC1061 to ampicillin resistance. The resulting plasmidpDD134, encodes the 445 bp synthetic gene for the alpha-factor-KPI(-4→57; M15L, I16F, S17K, G37Y) fusion.

W. Construction of pDD135 KPI (-4→57; M15L, I16F, S17K, G37L)

Plasmid pDD131 was digested with AatII and BamHI, and the larger of thetwo resulting fragments was isolated. An oligonucleotide pair (724+725)was phosphorylated, annealed and gel-purified as described previously.

724: (SEQ ID NO:72) CACTGAAGGTAAGTGCGCTCCATTCTTTTACGGCGGTTGCTTGGGCAACCGT; AACAACTTTGACACTGAAGAGTACTGCATGGCAGTGTGCG

725: (SEQ ID NO:73) GATCCGCACACTGCCATGCAGTACTCTTCAGTGTCAAAGTTGTTACGGTTGCCCAAGCAACCGCCGTAAAAGAATGGAGCGCACTTACCTTCAGTGACGT

The annealed oligonucleotides were ligated into the AatII andBamHI-digested pDD131, and the ligation product was used to transform E.coli strain MC1061 to ampicillin resistance. The resulting plasmidpDD135, encodes the 445 bp synthetic gene for the alpha-factor-KPI(-4→57; M15L, I16F, S17K, G37L) fusion.

Example 4 Kinetic Analysis of KPI(-4→57) Variants

The concentrations of active human plasma kallikrein, factor XIIa, andtrypsin were determined by titration with p-nitrophenylp'-guanidinobenzoate as described by Bender et al., supra, and Chase etal., Biochem. Biophys. Res. Conmmun. 29:508 (1967). Accurateconcentrations of active KPI(-4→57) inhibitors were determined bytitration of the activity of a known amount of active-site-titratedtrypsin. For testing against kallikrein and trypsin, each KPI(-4→57)variant (0.5 to 100 nM) was incubated with protease in low-binding96-well microtiter plates at 30° C. for 15-25 min, in 100 mM Tris-HCl,pH 7.5, with 500 mM NaCl, 5 mM KCl, 5 mM CaCl2, 5 mM MgCl12, 0.1% Difcogelatin, and 0.05% Triton X-100. Chromogenic synthetic substrate wasthen be added, and initial rates at 30° C. recorded by the SOFTmaxkinetics program via a THERMOmax microplate reader (Molecular DevicesCorp., Menlo Park, Calif.). The substrates used were N-α-benzoyl-L-Argp-nitroanilide (1 mM) for trypsin (20 nM), and N-benzoyl-Pro-Phe-Argp-nitroanilide (0.3 mM) for plasma kallikrein (1 nM). The Enzfitter(Elsevier) program was used both to plot fractional activity (i.e.,activity with inhibitor, divided by activity without inhibitor), a,versus total concentration of inhibitor, I_(t), and to calculate thedissociation constant of the inhibitor (K_(i)) by fitting the curve tothe following equation: ##EQU1##

The K_(i) s determined for purified KPI variants are shown in FIG. 45.The most potent variant, KPI (-4→57; M15A, S17F) DD185 is 115-fold morepotent as a human kallikrein inhibitor than wild-type KPI (-4→57). Theleast potent variant, KPI (-4→57; I16H, S17W) TW6185 is still 35-foldmore potent than wild-type KPI.

For testing against factor XIIa, essentially the same reactionconditions were used, except that the substrate wasN-benzoyl-Ile-Glu-Gly-Arg p-nitroaniline hydrochloride and its methylester (obtained from Pharmacia Hepar, Franklin, Ohio), and corn trypsininhibitor (Enzyme Research Laboratories, South Bend, Ind.) was used as acontrol inhibitor. Factor XIIa was also obtained from Enzyme ResearchLaboratories.

Various data for inhibition of the serine proteases of interestkallikrein, plasmin, and factors Xa, XIa, and XIIa by a series of KPIvariants are given in FIG. 46. The results indicate that KPI variantscan be produced that can bind to and preferably inhibit the activity ofserine proteases. The results also indicate that the peptides of theinvention may exhibit the preferable more potent and specific inhibitionof one or more serine proteases of interest.

Example 5 Effect of KPI Variant KPI185-1 on Postoperative Bleeding

A randomized, double-blinded study using an acute porcinecardiopulmonary bypass (CPB) model was used to investigate the effect ofKPI185-1 on postoperative bleeding. Sixteen pigs (55-65 kg) underwent 60minutes of hypothermic (28° C.) open-chest CPB with 30 minutes ofcardioplegic cardiac arrest. Pigs were randomized against a controlsolution of physiological saline (NS; n=8) or KPI-185(n=8) groups.During aortic cross-clamping, the tricuspid valve was inspected throughan atriotomy which was subsequently repaired. Following reversal ofheparin with protamine, dilateral thoracostomy tubes were placed andshed blood collected for 3 hours. Shed blood volume and hemoglobin (Hgb)loss were calculated from total chest tube output and residualintrathoracic blood at time of sacrifice.

Total blood loss was significantly reduced in the KPI185-1 group(245.75±66.24 ml vs. 344.25±63.97 ml, p=0.009). In addition, there was amarked reduction in total Hgb loss in the treatment group (13.59±4.26 gmvs. 23.61±4.69 gm, p=0.0005). Thoracostomy drainage Hgb wassignificantly increased at 30 and 60 minutes in the control group6.89±1.44 vs. 4.41±1.45 gm/dl (p=0.004) and 7.6±1.03 vs. 5.26±1.04 gm/dl(p=0.0002), respectively!. Preoperative and post-CPB hematocrits werenot statistically different between the groups. These results are shownin graphical form in FIGS. 4-50.

The invention has been disclosed broadly and illustrated in reference torepresentative embodiments described above. Those skilled in the artwill recognize that various modifications can be made to the presentinvention without departing from the spirit and scope thereof.

    __________________________________________________________________________    #             SEQUENCE LISTING    - (1) GENERAL INFORMATION:    -    (iii) NUMBER OF SEQUENCES: 228    - (2) INFORMATION FOR SEQ ID NO:1:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 57 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:    -      Xaa Val Cys Ser Glu Gln Ala Glu - # Xaa Gly Xaa Cys Arg Ala Xaa    Xaa    #   15    -      Xaa Xaa Trp Tyr Phe Asp Val Thr - # Glu Gly Lys Cys Ala Pro Phe    Xaa    #                 30    -      Tyr Gly Gly Cys Xaa Xaa Xaa Xaa - # Asn Asn Phe Asp Thr Glu Glu    Tyr    #             45    -      Cys Met Ala Val Cys Gly Ser Ala - # Ile    #         55    - (2) INFORMATION FOR SEQ ID NO:2:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 5 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:    -      Glu Val Val Arg Glu    #  5 1    - (2) INFORMATION FOR SEQ ID NO:3:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 57 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:    -      Xaa Val Cys Ser Glu Gln Ala Glu - # Thr Gly Pro Cys Arg Ala Xaa    Xaa    #   15    -      Xaa Arg Trp Tyr Phe Asp Val Thr - # Glu Gly Lys Cys Ala Pro Phe    Phe    #                 30    -      Tyr Gly Gly Cys Xaa Gly Asn Arg - # Asn Asn Phe Asp Thr Glu Glu    Tyr    #             45    -      Cys Met Ala Val Cys Gly Ser Ala - # Ile    #         55    - (2) INFORMATION FOR SEQ ID NO:4:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:    -      Glu Val Val Arg Glu Val Cys Ser - # Glu Gln Ala Glu Thr Gly Pro    Cys    #   15    -      Arg Ala Xaa Xaa Xaa Arg Trp Tyr - # Phe Asp Val Thr Glu Gly Lys    Cys    #                 30    -      Ala Pro Phe Phe Tyr Gly Gly Cys - # Xaa Gly Asn Arg Asn Asn Phe    Asp    #             45    -      Thr Glu Glu Tyr Cys Met Ala Val - # Cys Gly Ser Ala Ile    #         60    - (2) INFORMATION FOR SEQ ID NO:5:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 58 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:    -      Xaa Val Cys Ser Glu Gln Ala Glu - # Xaa Gly Pro Cys Arg Ala Xaa    Xaa    #   15    -      Xaa Xaa Arg Trp Tyr Phe Asp Val - # Thr Glu Gly Lys Cys Ala Pro    Phe    #                 30    -      Phe Tyr Gly Gly Cys Xaa Gly Asn - # Arg Asn Asn Phe Asp Thr Glu    Glu    #             45    -      Tyr Cys Met Ala Val Cys Gly Ser - # Ala Ile    #         55    - (2) INFORMATION FOR SEQ ID NO:6:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 59 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:    -      Val Arg Glu Val Cys Ser Glu Gln - # Ala Glu Thr Gly Pro Cys Arg    Ala    #   15    -      Met Ile Ser Arg Trp Tyr Phe Asp - # Val Thr Glu Gly Lys Cys Ala    Pro    #                 30    -      Phe Phe Tyr Gly Gly Cys Gly Gly - # Asn Arg Asn Asn Phe Asp Thr    Glu    #             45    -      Glu Tyr Cys Met Ala Val Cys Gly - # Ser Ala Ile    #         55    - (2) INFORMATION FOR SEQ ID NO:7:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 58 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:    -      Arg Pro Asp Phe Cys Leu Glu Pro - # Pro Tyr Thr Gly Pro Cys Lys    Ala    #   15    -      Arg Ile Ile Arg Tyr Phe Tyr Asn - # Ala Lys Ala Gly Leu Cys Gln    Thr    #                 30    -      Phe Val Tyr Gly Gly Cys Arg Ala - # Lys Arg Asn Asn Phe Lys Ser    Ala    #             45    -      Glu Asp Cys Met Arg Thr Cys Gly - # Gly Ala    #         55    - (2) INFORMATION FOR SEQ ID NO:8:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 4 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:    -      Glu Val Val Arg         1    - (2) INFORMATION FOR SEQ ID NO:9:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 79 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:    - TATGAAACAA AGCACTATTG CACTGGCACT CTTACCGTTA CTGTTTACCC CT - #GTGACAAA      60    # 79               GAA    - (2) INFORMATION FOR SEQ ID NO:10:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 67 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    #ID NO:10:(xi) SEQUENCE DESCRIPTION: SEQ    - CTCGGCTTTT GTCACAGGGG TAAACAGTAA CGGTAAGAGT GCCAGTGCAA TA - #GTGCTTTG      60    #          67    - (2) INFORMATION FOR SEQ ID NO:11:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 81 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:    - CAAGCTGAGA CCGGTCCGTG CCGTGCAATG ATCTCCCGCT GGTACTTTGA CG - #TCACTGAA      60    #81                TCTT T    - (2) INFORMATION FOR SEQ ID NO:12:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 81 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:    - GCACTTACCT TCAGTGACGT CAAAGTACCA GCGGGAGATC ATTGCACGGC AC - #GGACCGGT      60    #81                CACA C    - (2) INFORMATION FOR SEQ ID NO:13:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 81 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:    - TACGGCGGTT GCGGCGGCAA CCGTAACAAC TTTGACACTG AAGAGTACTG CA - #TGGCAGTG      60    #81                AAGC T    - (2) INFORMATION FOR SEQ ID NO:14:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 93 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:    - AGCTTAAATA GCGGATCCGC ACACTGCCAT GCAGTACTCT TCAGTGTCAA AG - #TTGTTACG      60    #         93       CCGT AAAAGAATGG AGC    - (2) INFORMATION FOR SEQ ID NO:15:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 37 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15:    #      37          TGTG CTCTGAACAA GCTGAGA    - (2) INFORMATION FOR SEQ ID NO:16:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 37 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16:    #      37          CAGA GCACACCTCT CTTTTAT    - (2) INFORMATION FOR SEQ ID NO:17:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 49 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:    #               49GTTGT TAGAGAGGTG TGCTCTGAAC AAGCTGAGA    - (2) INFORMATION FOR SEQ ID NO:18:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 49 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:    #               49TCAGA GCACACCTCT CTAACAACCT CTCTTTTAT    - (2) INFORMATION FOR SEQ ID NO:19:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 26 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19:    #              26  ACGA TTAAAA    - (2) INFORMATION FOR SEQ ID NO:20:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 30 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20:    #           30     CCCT TCTTCTTTAG    - (2) INFORMATION FOR SEQ ID NO:21:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 47 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21:    #                47CTGA GGCTCACGCT GAAGGTACTT TCACTTC    - (2) INFORMATION FOR SEQ ID NO:22:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 78 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22:    - TGACGTCTCT TCTTACTTGG AAGGTCAAGC TGCTAAGGAA TTCATCGCTT GG - #TTGGTCAA      60    #  78              TA    - (2) INFORMATION FOR SEQ ID NO:23:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 52 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:    - CTAGTAAGCT TAACCTCTAC CTTTGACCAA CCAAGCGATG AATTCCTTAG CA - #      52    - (2) INFORMATION FOR SEQ ID NO:24:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 73 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:    - GCTTGACCTT CCAAGTAAGA AGAGACGTCA GAAGTGAAAG TACCTTCAGC GT - #GAGCCTCA      60    #      73    - (2) INFORMATION FOR SEQ ID NO:25:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 40 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25:    #    40            TATC TGGCGCTGGT ACTTTGACGT    - (2) INFORMATION FOR SEQ ID NO:26:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 33 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26:    #         33       GATA GCTGCACGGC ACG    - (2) INFORMATION FOR SEQ ID NO:27:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 40 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27:    #    40            TATC TACCGCTGGT ACTTTGACGT    - (2) INFORMATION FOR SEQ ID NO:28:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 33 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28:    #         33       GATA GCTGCACGGC ACG    - (2) INFORMATION FOR SEQ ID NO:29:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 40 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29:    #    40            GATC TTCCGCTGGT ACTTTGACGT    - (2) INFORMATION FOR SEQ ID NO:30:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 33 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:30:    #         33       GATC AATGCACGGC ACG    - (2) INFORMATION FOR SEQ ID NO:31:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 40 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31:    #    40            GATC TACCGCTGGT ACTTTGACGT    - (2) INFORMATION FOR SEQ ID NO:32:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 33 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32:    #         33       GATC AAAGCACGGC ACG    - (2) INFORMATION FOR SEQ ID NO:33:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 40 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33:    #    40            GCAC TTCCGCTGGT ACTTTGACGT    - (2) INFORMATION FOR SEQ ID NO:34:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 33 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34:    #         33       GTGC ATTGCACGGC ACG    - (2) INFORMATION FOR SEQ ID NO:35:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 40 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:35:    #    40            GCAC TACCGCTGGT ACTTTGACGT    - (2) INFORMATION FOR SEQ ID NO:36:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 33 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:36:    #         33       GTGC ATTGCACGGC ACG    - (2) INFORMATION FOR SEQ ID NO:37:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 40 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37:    #    40            GCAC TGGCGCTGGT ACTTTGACGT    - (2) INFORMATION FOR SEQ ID NO:38:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 33 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:38:    #         33       GTGC ATTGCACGGC ACG    - (2) INFORMATION FOR SEQ ID NO:39:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 40 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:39:    #    40            TCAC TCCCGCTGGT ACTTTGACGT    - (2) INFORMATION FOR SEQ ID NO:40:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 33 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:40:    #         33       GTGA GCTGCACGGC ACG    - (2) INFORMATION FOR SEQ ID NO:41:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 40 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:41:    #    40            GCAC TCCCGCTGGT ACTTTGACGT    - (2) INFORMATION FOR SEQ ID NO:42:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 33 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:42:    #         33       GTGC AATGCACGGC ACG    - (2) INFORMATION FOR SEQ ID NO:43:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 38 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:43:    #     38           TAAG CGTCAGGTGG CACTTTTC    - (2) INFORMATION FOR SEQ ID NO:44:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 44 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:44:    # 44               TACG GGGTCTGACG CTCAGTGGAA CGAA    - (2) INFORMATION FOR SEQ ID NO:45:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 12 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:45:    #       12    - (2) INFORMATION FOR SEQ ID NO:46:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 11 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:46:    #       11    - (2) INFORMATION FOR SEQ ID NO:47:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 10 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:47:    #        10    - (2) INFORMATION FOR SEQ ID NO:48:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 11 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:48:    #       11    - (2) INFORMATION FOR SEQ ID NO:49:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 36 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:49:    #       36         CCGG TGGTGGCTCT GGTTCC    - (2) INFORMATION FOR SEQ ID NO:50:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 31 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:50:    #          31      CTCC TTATTACGCA G    - (2) INFORMATION FOR SEQ ID NO:51:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 39 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:51:    #    39            CCGG TGGTGGCTCT GGTTCCGGT    - (2) INFORMATION FOR SEQ ID NO:52:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 30 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:52:    #           30     TTAT TAAGACTCCT    - (2) INFORMATION FOR SEQ ID NO:53:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 27 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:53:    #             27   TGAA ACAAAGC    - (2) INFORMATION FOR SEQ ID NO:54:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 39 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:54:    #    39            CCCT AACCACGGCC TTTAACCAG    - (2) INFORMATION FOR SEQ ID NO:55:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 74 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:55:    - TATGAAACAA AGCACTATTG CACTGGCACT CTTACCGTTA CTGTTTACCC CG - #GTGACCAA      60    #     74    - (2) INFORMATION FOR SEQ ID NO:56:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 76 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:56:    - GTACCTTCAG CGTGGGCTTT GGTCACCGGG GTAAACAGTA ACGGTAAGAG TG - #CCAGTGCA      60    #    76    - (2) INFORMATION FOR SEQ ID NO:57:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 27 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:57:    #             27   TATC GTCACTG    - (2) INFORMATION FOR SEQ ID NO:58:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 29 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:58:    #            29    TAAA CAGTAACGG    - (2) INFORMATION FOR SEQ ID NO:59:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 42 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:59:    #  42              CCAA AGCCGAGGTG TGCTCTGAAC AA    - (2) INFORMATION FOR SEQ ID NO:60:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 36 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:60:    #       36         ACTG CCATGCAGTA CTCTTC    - (2) INFORMATION FOR SEQ ID NO:61:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 35 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:61:    #       35         TGGC CCGGCTCCAT GCACC    - (2) INFORMATION FOR SEQ ID NO:62:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 36 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:62:    #       36         ATCC TCGGCACCGT CACCCT    - (2) INFORMATION FOR SEQ ID NO:63:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 42 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:63:    #  42              GTGC CGTNCGCTGG TACTTTGACG TC    - (2) INFORMATION FOR SEQ ID NO:64:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 30 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:64:    #           30     ACAC TGCCATGCAG    - (2) INFORMATION FOR SEQ ID NO:65:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 4 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:65:    -      Ala Ala Ile Phe         1    - (2) INFORMATION FOR SEQ ID NO:66:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 41 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:66:    #   41             GCCG TNGCANTGGT ACTTTGACGT C    - (2) INFORMATION FOR SEQ ID NO:67:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 37 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:67:    #      37          GCCG TNTGGTACTT TGACGTC    - (2) INFORMATION FOR SEQ ID NO:68:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 52 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:68:    - CTAGATAAAA GAGAGGTTGT TAGAGAGGTG TGCTCTGAAC AAGCTGAGGT TG - #      52    - (2) INFORMATION FOR SEQ ID NO:69:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 51 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:69:    #             51TTGTTCA GAGCACACCT CTCTAACAAC CTCTCTTTTA T    - (2) INFORMATION FOR SEQ ID NO:70:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 92 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:70:    - CACTGAAGGT AAGTGCGCTC CATTCTTTTA CGGCGGTTGC TACGGCAACC GT - #AACAACTT      60    #          92      TGCA TGGCAGTGTG CG    - (2) INFORMATION FOR SEQ ID NO:71:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 100 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:71:    - GATCCGCACA CTGCCATGCA GTACTCTTCA GTGTCAAAGT TGTTACGGTT GC - #CGTAGCAA      60    #   100            GAGC GCACTTACCT TCAGTGACGT    - (2) INFORMATION FOR SEQ ID NO:72:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 92 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:72:    - CACTGAAGGT AAGTGCGCTC CATTCTTTTA CGGCGGTTGC TTGGGCAACC GT - #AACAACTT      60    #          92      TGCA TGGCAGTGTG CG    - (2) INFORMATION FOR SEQ ID NO:73:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 100 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:73:    - GATCCGCACA CTGCCATGCA GTACTCTTCA GTGTCAAAGT TGTTACGGTT GC - #CCAAGCAA      60    #   100            GAGC GCACTTACCT TCAGTGACGT    - (2) INFORMATION FOR SEQ ID NO:74:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 237 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (ix) FEATURE:              (A) NAME/KEY: CDS              (B) LOCATION: 2..235    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:74:    #TTA CCG TTA CTG TTT         46 CTG GCA CTC      Met Lys Gln Ser Thr Ile Ala Leu Ala L - #eu Leu Pro Leu Leu Phe    # 15    - ACC CCT GTG ACA AAA GCC GAG GTG TGC TCT GA - #A CAA GCT GAG ACC GGT      94    Thr Pro Val Thr Lys Ala Glu Val Cys Ser Gl - #u Gln Ala Glu Thr Gly    #                 30    - CCG TGC CGT GCA ATG ATC TCC CGC TGG TAC TT - #T GAC GTC ACT GAA GGT     142    Pro Cys Arg Ala Met Ile Ser Arg Trp Tyr Ph - #e Asp Val Thr Glu Gly    #             45    - AAG TGC GCT CCA TTC TTT TAC GGC GGT TGC GG - #C GGC AAC CGT AAC AAC     190    Lys Cys Ala Pro Phe Phe Tyr Gly Gly Cys Gl - #y Gly Asn Arg Asn Asn    #         60    - TTT GAC ACT GAA GAG TAC TGC ATG GCA GTG TG - #C GGA TCC GCT ATT     23 - #5    Phe Asp Thr Glu Glu Tyr Cys Met Ala Val Cy - #s Gly Ser Ala Ile    #     75    #             237    - (2) INFORMATION FOR SEQ ID NO:75:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 78 amino              (B) TYPE: amino acid              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:75:    - Met Lys Gln Ser Thr Ile Ala Leu Ala Leu Le - #u Pro Leu Leu Phe Thr    #                 15    - Pro Val Thr Lys Ala Glu Val Cys Ser Glu Gl - #n Ala Glu Thr Gly Pro    #             30    - Cys Arg Ala Met Ile Ser Arg Trp Tyr Phe As - #p Val Thr Glu Gly Lys    #         45    - Cys Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gl - #y Asn Arg Asn Asn Phe    #     60    - Asp Thr Glu Glu Tyr Cys Met Ala Val Cys Gl - #y Ser Ala Ile    # 75    - (2) INFORMATION FOR SEQ ID NO:76:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 185 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (ix) FEATURE:              (A) NAME/KEY: CDS              (B) LOCATION: 1..183    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:76:    - CTA GAT AAA AGA GAG GTG TGC TCT GAA CAA GC - #T GAG ACC GGT CCG TGC      48    Leu Asp Lys Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #     90    - CGT GCA ATG ATC TCC CGC TGG TAC TTT GAC GT - #C ACT GAA GGT AAG TGC      96    Arg Ala Met Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #110    - GCT CCA TTC TTT TAC GGC GGT TGC GGC GGC AA - #C CGT AAC AAC TTT GAC     144    Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #               125    #  185GAA GAG TAC TGC ATG GCA GTG TGC GGA TC - #C GCT ATT TA    Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #           135    - (2) INFORMATION FOR SEQ ID NO:77:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:77:    - Leu Asp Lys Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                 15    - Arg Ala Met Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #             30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #         45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #     60    - (2) INFORMATION FOR SEQ ID NO:78:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 197 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (ix) FEATURE:              (A) NAME/KEY: CDS              (B) LOCATION: 1..195    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:78:    - CTA GAT AAA AGA GAG GTT GTT AGA GAG GTG TG - #C TCT GAA CAA GCT GAG      48    Leu Asp Lys Arg Glu Val Val Arg Glu Val Cy - #s Ser Glu Gln Ala Glu    #             75    - ACC GGT CCG TGC CGT GCA ATG ATC TCC CGC TG - #G TAC TTT GAC GTC ACT      96    Thr Gly Pro Cys Arg Ala Met Ile Ser Arg Tr - #p Tyr Phe Asp Val Thr    #         90    - GAA GGT AAG TGC GCT CCA TTC TTT TAC GGC GG - #T TGC GGC GGC AAC CGT     144    Glu Gly Lys Cys Ala Pro Phe Phe Tyr Gly Gl - #y Cys Gly Gly Asn Arg    #    105    - AAC AAC TTT GAC ACT GAA GAG TAC TGC ATG GC - #A GTG TGC GGA TCC GCT     192    Asn Asn Phe Asp Thr Glu Glu Tyr Cys Met Al - #a Val Cys Gly Ser Ala    110                 1 - #15                 1 - #20                 1 -    #25    #           197    Ile    - (2) INFORMATION FOR SEQ ID NO:79:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 65 amino              (B) TYPE: amino acid              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    #NO:79: (xi) SEQUENCE DESCRIPTION: SEQ ID    - Leu Asp Lys Arg Glu Val Val Arg Glu Val Cy - #s Ser Glu Gln Ala Glu    #                 15    - Thr Gly Pro Cys Arg Ala Met Ile Ser Arg Tr - #p Tyr Phe Asp Val Thr    #             30    - Glu Gly Lys Cys Ala Pro Phe Phe Tyr Gly Gl - #y Cys Gly Gly Asn Arg    #         45    - Asn Asn Phe Asp Thr Glu Glu Tyr Cys Met Al - #a Val Cys Gly Ser Ala    #     60    - Ile     65    - (2) INFORMATION FOR SEQ ID NO:80:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 445 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (ix) FEATURE:              (A) NAME/KEY: CDS              (B) LOCATION: 1..438    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:80:    - ATG AGA TTT CCT TCA ATT TTT ACT GCA GTT TT - #A TTC GCA GCA TCC TCC      48    Met Arg Phe Pro Ser Ile Phe Thr Ala Val Le - #u Phe Ala Ala Ser Ser    #                 80    - GCA TTA GCT GCT CCA GTC AAC ACT ACA ACA GA - #A GAT GAA ACG GCA CAA      96    Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Gl - #u Asp Glu Thr Ala Gln    #             95    - ATT CCG GCT GAA GCT GTC ATC GGT TAC TTA GA - #T TTA GAA GGG GAT TTC     144    Ile Pro Ala Glu Ala Val Ile Gly Tyr Leu As - #p Leu Glu Gly Asp Phe    #       110    - GAT GTT GCT GTT TTG CCA TTT TCC AAC AGC AC - #A AAT AAC GGG TTA TTG     192    Asp Val Ala Val Leu Pro Phe Ser Asn Ser Th - #r Asn Asn Gly Leu Leu    #   125    - TTT ATA AAT ACT ACT ATT GCC AGC ATT GCT GC - #T AAA GAA GAA GGG GTA     240    Phe Ile Asn Thr Thr Ile Ala Ser Ile Ala Al - #a Lys Glu Glu Gly Val    130                 1 - #35                 1 - #40                 1 -    #45    - TCT CTA GAT AAA AGA GAG GTT GTT AGA GAG GT - #G TGC TCT GAA CAA GCT     288    Ser Leu Asp Lys Arg Glu Val Val Arg Glu Va - #l Cys Ser Glu Gln Ala    #               160    - GAG ACC GGT CCG TGC CGT GCA ATG ATC TCC CG - #C TGG TAC TTT GAC GTC     336    Glu Thr Gly Pro Cys Arg Ala Met Ile Ser Ar - #g Trp Tyr Phe Asp Val    #           175    - ACT GAA GGT AAG TGC GCT CCA TTC TTT TAC GG - #C GGT TGC GGC GGC AAC     384    Thr Glu Gly Lys Cys Ala Pro Phe Phe Tyr Gl - #y Gly Cys Gly Gly Asn    #       190    - CGT AAC AAC TTT GAC ACT GAA GAG TAC TGC AT - #G GCA GTG TGC GGA TCC     432    Arg Asn Asn Phe Asp Thr Glu Glu Tyr Cys Me - #t Ala Val Cys Gly Ser    #   205    #     445    Ala Ile    210    - (2) INFORMATION FOR SEQ ID NO:81:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 146 amino              (B) TYPE: amino acid              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:81:    - Met Arg Phe Pro Ser Ile Phe Thr Ala Val Le - #u Phe Ala Ala Ser Ser    #                 15    - Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Gl - #u Asp Glu Thr Ala Gln    #             30    - Ile Pro Ala Glu Ala Val Ile Gly Tyr Leu As - #p Leu Glu Gly Asp Phe    #         45    - Asp Val Ala Val Leu Pro Phe Ser Asn Ser Th - #r Asn Asn Gly Leu Leu    #     60    - Phe Ile Asn Thr Thr Ile Ala Ser Ile Ala Al - #a Lys Glu Glu Gly Val    # 80    - Ser Leu Asp Lys Arg Glu Val Val Arg Glu Va - #l Cys Ser Glu Gln Ala    #                 95    - Glu Thr Gly Pro Cys Arg Ala Met Ile Ser Ar - #g Trp Tyr Phe Asp Val    #           110    - Thr Glu Gly Lys Cys Ala Pro Phe Phe Tyr Gl - #y Gly Cys Gly Gly Asn    #       125    - Arg Asn Asn Phe Asp Thr Glu Glu Tyr Cys Me - #t Ala Val Cys Gly Ser    #   140    - Ala Ile    145    - (2) INFORMATION FOR SEQ ID NO:82:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 445 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (ix) FEATURE:              (A) NAME/KEY: CDS              (B) LOCATION: 1..438    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:82:    - ATG AGA TTT CCT TCA ATT TTT ACT GCA GTT TT - #A TTC GCA GCA TCC TCC      48    Met Arg Phe Pro Ser Ile Phe Thr Ala Val Le - #u Phe Ala Ala Ser Ser    #           160    - GCA TTA GCT GCT CCA GTC AAC ACT ACA ACA GA - #A GAT GAA ACG GCA CAA      96    Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Gl - #u Asp Glu Thr Ala Gln    #       175    - ATT CCG GCT GAA GCT GTC ATC GGT TAC TTA GA - #T TTA GAA GGG GAT TTC     144    Ile Pro Ala Glu Ala Val Ile Gly Tyr Leu As - #p Leu Glu Gly Asp Phe    #   190    - GAT GTT GCT GTT TTG CCA TTT TCC AAC AGC AC - #A AAT AAC GGG TTA TTG     192    Asp Val Ala Val Leu Pro Phe Ser Asn Ser Th - #r Asn Asn Gly Leu Leu    195                 2 - #00                 2 - #05                 2 -    #10    - TTT ATA AAT ACT ACT ATT GCC AGC ATT GCT GC - #T AAA GAA GAA GGG GTA     240    Phe Ile Asn Thr Thr Ile Ala Ser Ile Ala Al - #a Lys Glu Glu Gly Val    #               225    - TCT CTA GAT AAA AGA GAG GTT GTT AGA GAG GT - #G TGC TCT GAA CAA GCT     288    Ser Leu Asp Lys Arg Glu Val Val Arg Glu Va - #l Cys Ser Glu Gln Ala    #           240    - GAG ACC GGT CCG TGC CGT GCA GCT ATC TGG CG - #C TGG TAC TTT GAC GTC     336    Glu Thr Gly Pro Cys Arg Ala Ala Ile Trp Ar - #g Trp Tyr Phe Asp Val    #       255    - ACT GAA GGT AAG TGC GCT CCA TTC TTT TAC GG - #C GGT TGC GGC GGC AAC     384    Thr Glu Gly Lys Cys Ala Pro Phe Phe Tyr Gl - #y Gly Cys Gly Gly Asn    #   270    - CGT AAC AAC TTT GAC ACT GAA GAG TAC TGC AT - #G GCA GTG TGC GGA TCC     432    Arg Asn Asn Phe Asp Thr Glu Glu Tyr Cys Me - #t Ala Val Cys Gly Ser    275                 2 - #80                 2 - #85                 2 -    #90    #     445    Ala Ile    - (2) INFORMATION FOR SEQ ID NO:83:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 146 amino              (B) TYPE: amino acid              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:83:    - Met Arg Phe Pro Ser Ile Phe Thr Ala Val Le - #u Phe Ala Ala Ser Ser    #                 15    - Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Gl - #u Asp Glu Thr Ala Gln    #             30    - Ile Pro Ala Glu Ala Val Ile Gly Tyr Leu As - #p Leu Glu Gly Asp Phe    #         45    - Asp Val Ala Val Leu Pro Phe Ser Asn Ser Th - #r Asn Asn Gly Leu Leu    #     60    - Phe Ile Asn Thr Thr Ile Ala Ser Ile Ala Al - #a Lys Glu Glu Gly Val    # 80    - Ser Leu Asp Lys Arg Glu Val Val Arg Glu Va - #l Cys Ser Glu Gln Ala    #                 95    - Glu Thr Gly Pro Cys Arg Ala Ala Ile Trp Ar - #g Trp Tyr Phe Asp Val    #           110    - Thr Glu Gly Lys Cys Ala Pro Phe Phe Tyr Gl - #y Gly Cys Gly Gly Asn    #       125    - Arg Asn Asn Phe Asp Thr Glu Glu Tyr Cys Me - #t Ala Val Cys Gly Ser    #   140    - Ala Ile    145    - (2) INFORMATION FOR SEQ ID NO:84:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 445 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (ix) FEATURE:              (A) NAME/KEY: CDS              (B) LOCATION: 1..438    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:84:    - ATG AGA TTT CCT TCA ATT TTT ACT GCA GTT TT - #A TTC GCA GCA TCC TCC      48    Met Arg Phe Pro Ser Ile Phe Thr Ala Val Le - #u Phe Ala Ala Ser Ser    #           160    - GCA TTA GCT GCT CCA GTC AAC ACT ACA ACA GA - #A GAT GAA ACG GCA CAA      96    Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Gl - #u Asp Glu Thr Ala Gln    #       175    - ATT CCG GCT GAA GCT GTC ATC GGT TAC TTA GA - #T TTA GAA GGG GAT TTC     144    Ile Pro Ala Glu Ala Val Ile Gly Tyr Leu As - #p Leu Glu Gly Asp Phe    #   190    - GAT GTT GCT GTT TTG CCA TTT TCC AAC AGC AC - #A AAT AAC GGG TTA TTG     192    Asp Val Ala Val Leu Pro Phe Ser Asn Ser Th - #r Asn Asn Gly Leu Leu    195                 2 - #00                 2 - #05                 2 -    #10    - TTT ATA AAT ACT ACT ATT GCC AGC ATT GCT GC - #T AAA GAA GAA GGG GTA     240    Phe Ile Asn Thr Thr Ile Ala Ser Ile Ala Al - #a Lys Glu Glu Gly Val    #               225    - TCT CTA GAT AAA AGA GAG GTT GTT AGA GAG GT - #G TGC TCT GAA CAA GCT     288    Ser Leu Asp Lys Arg Glu Val Val Arg Glu Va - #l Cys Ser Glu Gln Ala    #           240    - GAG ACC GGT CCG TGC CGT GCA GCT ATC TAC CG - #C TGG TAC TTT GAC GTC     336    Glu Thr Gly Pro Cys Arg Ala Ala Ile Tyr Ar - #g Trp Tyr Phe Asp Val    #       255    - ACT GAA GGT AAG TGC GCT CCA TTC TTT TAC GG - #C GGT TGC GGC GGC AAC     384    Thr Glu Gly Lys Cys Ala Pro Phe Phe Tyr Gl - #y Gly Cys Gly Gly Asn    #   270    - CGT AAC AAC TTT GAC ACT GAA GAG TAC TGC AT - #G GCA GTG TGC GGA TCC     432    Arg Asn Asn Phe Asp Thr Glu Glu Tyr Cys Me - #t Ala Val Cys Gly Ser    275                 2 - #80                 2 - #85                 2 -    #90    #     445    Ala Ile    - (2) INFORMATION FOR SEQ ID NO:85:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 146 amino              (B) TYPE: amino acid              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:85:    - Met Arg Phe Pro Ser Ile Phe Thr Ala Val Le - #u Phe Ala Ala Ser Ser    #                 15    - Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Gl - #u Asp Glu Thr Ala Gln    #             30    - Ile Pro Ala Glu Ala Val Ile Gly Tyr Leu As - #p Leu Glu Gly Asp Phe    #         45    - Asp Val Ala Val Leu Pro Phe Ser Asn Ser Th - #r Asn Asn Gly Leu Leu    #     60    - Phe Ile Asn Thr Thr Ile Ala Ser Ile Ala Al - #a Lys Glu Glu Gly Val    # 80    - Ser Leu Asp Lys Arg Glu Val Val Arg Glu Va - #l Cys Ser Glu Gln Ala    #                 95    - Glu Thr Gly Pro Cys Arg Ala Ala Ile Tyr Ar - #g Trp Tyr Phe Asp Val    #           110    - Thr Glu Gly Lys Cys Ala Pro Phe Phe Tyr Gl - #y Gly Cys Gly Gly Asn    #       125    - Arg Asn Asn Phe Asp Thr Glu Glu Tyr Cys Me - #t Ala Val Cys Gly Ser    #   140    - Ala Ile    145    - (2) INFORMATION FOR SEQ ID NO:86:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 445 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (ix) FEATURE:              (A) NAME/KEY: CDS              (B) LOCATION: 1..438    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:86:    - ATG AGA TTT CCT TCA ATT TTT ACT GCA GTT TT - #A TTC GCA GCA TCC TCC      48    Met Arg Phe Pro Ser Ile Phe Thr Ala Val Le - #u Phe Ala Ala Ser Ser    #           160    - GCA TTA GCT GCT CCA GTC AAC ACT ACA ACA GA - #A GAT GAA ACG GCA CAA      96    Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Gl - #u Asp Glu Thr Ala Gln    #       175    - ATT CCG GCT GAA GCT GTC ATC GGT TAC TTA GA - #T TTA GAA GGG GAT TTC     144    Ile Pro Ala Glu Ala Val Ile Gly Tyr Leu As - #p Leu Glu Gly Asp Phe    #   190    - GAT GTT GCT GTT TTG CCA TTT TCC AAC AGC AC - #A AAT AAC GGG TTA TTG     192    Asp Val Ala Val Leu Pro Phe Ser Asn Ser Th - #r Asn Asn Gly Leu Leu    195                 2 - #00                 2 - #05                 2 -    #10    - TTT ATA AAT ACT ACT ATT GCC AGC ATT GCT GC - #T AAA GAA GAA GGG GTA     240    Phe Ile Asn Thr Thr Ile Ala Ser Ile Ala Al - #a Lys Glu Glu Gly Val    #               225    - TCT CTA GAT AAA AGA GAG GTT GTT AGA GAG GT - #G TGC TCT GAA CAA GCT     288    Ser Leu Asp Lys Arg Glu Val Val Arg Glu Va - #l Cys Ser Glu Gln Ala    #           240    - GAG ACC GGT CCG TGC CGT GCA TTG ATC TTC CG - #C TGG TAC TTT GAC GTC     336    Glu Thr Gly Pro Cys Arg Ala Leu Ile Phe Ar - #g Trp Tyr Phe Asp Val    #       255    - ACT GAA GGT AAG TGC GCT CCA TTC TTT TAC GG - #C GGT TGC GGC GGC AAC     384    Thr Glu Gly Lys Cys Ala Pro Phe Phe Tyr Gl - #y Gly Cys Gly Gly Asn    #   270    - CGT AAC AAC TTT GAC ACT GAA GAG TAC TGC AT - #G GCA GTG TGC GGA TCC     432    Arg Asn Asn Phe Asp Thr Glu Glu Tyr Cys Me - #t Ala Val Cys Gly Ser    275                 2 - #80                 2 - #85                 2 -    #90    #     445    Ala Ile    - (2) INFORMATION FOR SEQ ID NO:87:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 146 amino              (B) TYPE: amino acid              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:87:    - Met Arg Phe Pro Ser Ile Phe Thr Ala Val Le - #u Phe Ala Ala Ser Ser    #                 15    - Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Gl - #u Asp Glu Thr Ala Gln    #             30    - Ile Pro Ala Glu Ala Val Ile Gly Tyr Leu As - #p Leu Glu Gly Asp Phe    #         45    - Asp Val Ala Val Leu Pro Phe Ser Asn Ser Th - #r Asn Asn Gly Leu Leu    #     60    - Phe Ile Asn Thr Thr Ile Ala Ser Ile Ala Al - #a Lys Glu Glu Gly Val    # 80    - Ser Leu Asp Lys Arg Glu Val Val Arg Glu Va - #l Cys Ser Glu Gln Ala    #                 95    - Glu Thr Gly Pro Cys Arg Ala Leu Ile Phe Ar - #g Trp Tyr Phe Asp Val    #           110    - Thr Glu Gly Lys Cys Ala Pro Phe Phe Tyr Gl - #y Gly Cys Gly Gly Asn    #       125    - Arg Asn Asn Phe Asp Thr Glu Glu Tyr Cys Me - #t Ala Val Cys Gly Ser    #   140    - Ala Ile    145    - (2) INFORMATION FOR SEQ ID NO:88:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 445 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (ix) FEATURE:              (A) NAME/KEY: CDS              (B) LOCATION: 1..438    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:88:    - ATG AGA TTT CCT TCA ATT TTT ACT GCA GTT TT - #A TTC GCA GCA TCC TCC      48    Met Arg Phe Pro Ser Ile Phe Thr Ala Val Le - #u Phe Ala Ala Ser Ser    #           160    - GCA TTA GCT GCT CCA GTC AAC ACT ACA ACA GA - #A GAT GAA ACG GCA CAA      96    Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Gl - #u Asp Glu Thr Ala Gln    #       175    - ATT CCG GCT GAA GCT GTC ATC GGT TAC TTA GA - #T TTA GAA GGG GAT TTC     144    Ile Pro Ala Glu Ala Val Ile Gly Tyr Leu As - #p Leu Glu Gly Asp Phe    #   190    - GAT GTT GCT GTT TTG CCA TTT TCC AAC AGC AC - #A AAT AAC GGG TTA TTG     192    Asp Val Ala Val Leu Pro Phe Ser Asn Ser Th - #r Asn Asn Gly Leu Leu    195                 2 - #00                 2 - #05                 2 -    #10    - TTT ATA AAT ACT ACT ATT GCC AGC ATT GCT GC - #T AAA GAA GAA GGG GTA     240    Phe Ile Asn Thr Thr Ile Ala Ser Ile Ala Al - #a Lys Glu Glu Gly Val    #               225    - TCT CTA GAT AAA AGA GAG GTT GTT AGA GAG GT - #G TGC TCT GAA CAA GCT     288    Ser Leu Asp Lys Arg Glu Val Val Arg Glu Va - #l Cys Ser Glu Gln Ala    #           240    - GAG ACC GGT CCG TGC CGT GCA TTG ATC TAC CG - #C TGG TAC TTT GAC GTC     336    Glu Thr Gly Pro Cys Arg Ala Leu Ile Tyr Ar - #g Trp Tyr Phe Asp Val    #       255    - ACT GAA GGT AAG TGC GCT CCA TTC TTT TAC GG - #C GGT TGC GGC GGC AAC     384    Thr Glu Gly Lys Cys Ala Pro Phe Phe Tyr Gl - #y Gly Cys Gly Gly Asn    #   270    - CGT AAC AAC TTT GAC ACT GAA GAG TAC TGC AT - #G GCA GTG TGC GGA TCC     432    Arg Asn Asn Phe Asp Thr Glu Glu Tyr Cys Me - #t Ala Val Cys Gly Ser    275                 2 - #80                 2 - #85                 2 -    #90    #     445    Ala Ile    - (2) INFORMATION FOR SEQ ID NO:89:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 146 amino              (B) TYPE: amino acid              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:89:    - Met Arg Phe Pro Ser Ile Phe Thr Ala Val Le - #u Phe Ala Ala Ser Ser    #                 15    - Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Gl - #u Asp Glu Thr Ala Gln    #             30    - Ile Pro Ala Glu Ala Val Ile Gly Tyr Leu As - #p Leu Glu Gly Asp Phe    #         45    - Asp Val Ala Val Leu Pro Phe Ser Asn Ser Th - #r Asn Asn Gly Leu Leu    #     60    - Phe Ile Asn Thr Thr Ile Ala Ser Ile Ala Al - #a Lys Glu Glu Gly Val    # 80    - Ser Leu Asp Lys Arg Glu Val Val Arg Glu Va - #l Cys Ser Glu Gln Ala    #                 95    - Glu Thr Gly Pro Cys Arg Ala Leu Ile Tyr Ar - #g Trp Tyr Phe Asp Val    #           110    - Thr Glu Gly Lys Cys Ala Pro Phe Phe Tyr Gl - #y Gly Cys Gly Gly Asn    #       125    - Arg Asn Asn Phe Asp Thr Glu Glu Tyr Cys Me - #t Ala Val Cys Gly Ser    #   140    - Ala Ile    145    - (2) INFORMATION FOR SEQ ID NO:90:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 445 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (ix) FEATURE:              (A) NAME/KEY: CDS              (B) LOCATION: 1..438    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:90:    - ATG AGA TTT CCT TCA ATT TTT ACT GCA GTT TT - #A TTC GCA GCA TCC TCC      48    Met Arg Phe Pro Ser Ile Phe Thr Ala Val Le - #u Phe Ala Ala Ser Ser    #           160    - GCA TTA GCT GCT CCA GTC AAC ACT ACA ACA GA - #A GAT GAA ACG GCA CAA      96    Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Gl - #u Asp Glu Thr Ala Gln    #       175    - ATT CCG GCT GAA GCT GTC ATC GGT TAC TTA GA - #T TTA GAA GGG GAT TTC     144    Ile Pro Ala Glu Ala Val Ile Gly Tyr Leu As - #p Leu Glu Gly Asp Phe    #   190    - GAT GTT GCT GTT TTG CCA TTT TCC AAC AGC AC - #A AAT AAC GGG TTA TTG     192    Asp Val Ala Val Leu Pro Phe Ser Asn Ser Th - #r Asn Asn Gly Leu Leu    195                 2 - #00                 2 - #05                 2 -    #10    - TTT ATA AAT ACT ACT ATT GCC AGC ATT GCT GC - #T AAA GAA GAA GGG GTA     240    Phe Ile Asn Thr Thr Ile Ala Ser Ile Ala Al - #a Lys Glu Glu Gly Val    #               225    - TCT CTA GAT AAA AGA GAG GTT GTT AGA GAG GT - #G TGC TCT GAA CAA GCT     288    Ser Leu Asp Lys Arg Glu Val Val Arg Glu Va - #l Cys Ser Glu Gln Ala    #           240    - GAG ACC GGT CCG TGC CGT GCA ATG CAC TTC CG - #C TGG TAC TTT GAC GTC     336    Glu Thr Gly Pro Cys Arg Ala Met His Phe Ar - #g Trp Tyr Phe Asp Val    #       255    - ACT GAA GGT AAG TGC GCT CCA TTC TTT TAC GG - #C GGT TGC GGC GGC AAC     384    Thr Glu Gly Lys Cys Ala Pro Phe Phe Tyr Gl - #y Gly Cys Gly Gly Asn    #   270    - CGT AAC AAC TTT GAC ACT GAA GAG TAC TGC AT - #G GCA GTG TGC GGA TCC     432    Arg Asn Asn Phe Asp Thr Glu Glu Tyr Cys Me - #t Ala Val Cys Gly Ser    275                 2 - #80                 2 - #85                 2 -    #90    #     445    Ala Ile    - (2) INFORMATION FOR SEQ ID NO:91:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 146 amino              (B) TYPE: amino acid              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:91:    - Met Arg Phe Pro Ser Ile Phe Thr Ala Val Le - #u Phe Ala Ala Ser Ser    #                 15    - Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Gl - #u Asp Glu Thr Ala Gln    #             30    - Ile Pro Ala Glu Ala Val Ile Gly Tyr Leu As - #p Leu Glu Gly Asp Phe    #         45    - Asp Val Ala Val Leu Pro Phe Ser Asn Ser Th - #r Asn Asn Gly Leu Leu    #     60    - Phe Ile Asn Thr Thr Ile Ala Ser Ile Ala Al - #a Lys Glu Glu Gly Val    # 80    - Ser Leu Asp Lys Arg Glu Val Val Arg Glu Va - #l Cys Ser Glu Gln Ala    #                 95    - Glu Thr Gly Pro Cys Arg Ala Met His Phe Ar - #g Trp Tyr Phe Asp Val    #           110    - Thr Glu Gly Lys Cys Ala Pro Phe Phe Tyr Gl - #y Gly Cys Gly Gly Asn    #       125    - Arg Asn Asn Phe Asp Thr Glu Glu Tyr Cys Me - #t Ala Val Cys Gly Ser    #   140    - Ala Ile    145    - (2) INFORMATION FOR SEQ ID NO:92:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 445 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (ix) FEATURE:              (A) NAME/KEY: CDS              (B) LOCATION: 1..438    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:92:    - ATG AGA TTT CCT TCA ATT TTT ACT GCA GTT TT - #A TTC GCA GCA TCC TCC      48    Met Arg Phe Pro Ser Ile Phe Thr Ala Val Le - #u Phe Ala Ala Ser Ser    #           160    - GCA TTA GCT GCT CCA GTC AAC ACT ACA ACA GA - #A GAT GAA ACG GCA CAA      96    Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Gl - #u Asp Glu Thr Ala Gln    #       175    - ATT CCG GCT GAA GCT GTC ATC GGT TAC TTA GA - #T TTA GAA GGG GAT TTC     144    Ile Pro Ala Glu Ala Val Ile Gly Tyr Leu As - #p Leu Glu Gly Asp Phe    #   190    - GAT GTT GCT GTT TTG CCA TTT TCC AAC AGC AC - #A AAT AAC GGG TTA TTG     192    Asp Val Ala Val Leu Pro Phe Ser Asn Ser Th - #r Asn Asn Gly Leu Leu    195                 2 - #00                 2 - #05                 2 -    #10    - TTT ATA AAT ACT ACT ATT GCC AGC ATT GCT GC - #T AAA GAA GAA GGG GTA     240    Phe Ile Asn Thr Thr Ile Ala Ser Ile Ala Al - #a Lys Glu Glu Gly Val    #               225    - TCT CTA GAT AAA AGA GAG GTT GTT AGA GAG GT - #G TGC TCT GAA CAA GCT     288    Ser Leu Asp Lys Arg Glu Val Val Arg Glu Va - #l Cys Ser Glu Gln Ala    #           240    - GAG ACC GGT CCG TGC CGT GCA ATG CAC TAC CG - #C TGG TAC TTT GAC GTC     336    Glu Thr Gly Pro Cys Arg Ala Met His Tyr Ar - #g Trp Tyr Phe Asp Val    #       255    - ACT GAA GGT AAG TGC GCT CCA TTC TTT TAC GG - #C GGT TGC GGC GGC AAC     384    Thr Glu Gly Lys Cys Ala Pro Phe Phe Tyr Gl - #y Gly Cys Gly Gly Asn    #   270    - CGT AAC AAC TTT GAC ACT GAA GAG TAC TGC AT - #G GCA GTG TGC GGA TCC     432    Arg Asn Asn Phe Asp Thr Glu Glu Tyr Cys Me - #t Ala Val Cys Gly Ser    275                 2 - #80                 2 - #85                 2 -    #90    #     445    Ala Ile    - (2) INFORMATION FOR SEQ ID NO:93:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 146 amino              (B) TYPE: amino acid              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:93:    - Met Arg Phe Pro Ser Ile Phe Thr Ala Val Le - #u Phe Ala Ala Ser Ser    #                 15    - Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Gl - #u Asp Glu Thr Ala Gln    #             30    - Ile Pro Ala Glu Ala Val Ile Gly Tyr Leu As - #p Leu Glu Gly Asp Phe    #         45    - Asp Val Ala Val Leu Pro Phe Ser Asn Ser Th - #r Asn Asn Gly Leu Leu    #     60    - Phe Ile Asn Thr Thr Ile Ala Ser Ile Ala Al - #a Lys Glu Glu Gly Val    # 80    - Ser Leu Asp Lys Arg Glu Val Val Arg Glu Va - #l Cys Ser Glu Gln Ala    #                 95    - Glu Thr Gly Pro Cys Arg Ala Met His Tyr Ar - #g Trp Tyr Phe Asp Val    #           110    - Thr Glu Gly Lys Cys Ala Pro Phe Phe Tyr Gl - #y Gly Cys Gly Gly Asn    #       125    - Arg Asn Asn Phe Asp Thr Glu Glu Tyr Cys Me - #t Ala Val Cys Gly Ser    #   140    - Ala Ile    145    - (2) INFORMATION FOR SEQ ID NO:94:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 445 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (ix) FEATURE:              (A) NAME/KEY: CDS              (B) LOCATION: 1..438    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:94:    - ATG AGA TTT CCT TCA ATT TTT ACT GCA GTT TT - #A TTC GCA GCA TCC TCC      48    Met Arg Phe Pro Ser Ile Phe Thr Ala Val Le - #u Phe Ala Ala Ser Ser    #           160    - GCA TTA GCT GCT CCA GTC AAC ACT ACA ACA GA - #A GAT GAA ACG GCA CAA      96    Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Gl - #u Asp Glu Thr Ala Gln    #       175    - ATT CCG GCT GAA GCT GTC ATC GGT TAC TTA GA - #T TTA GAA GGG GAT TTC     144    Ile Pro Ala Glu Ala Val Ile Gly Tyr Leu As - #p Leu Glu Gly Asp Phe    #   190    - GAT GTT GCT GTT TTG CCA TTT TCC AAC AGC AC - #A AAT AAC GGG TTA TTG     192    Asp Val Ala Val Leu Pro Phe Ser Asn Ser Th - #r Asn Asn Gly Leu Leu    195                 2 - #00                 2 - #05                 2 -    #10    - TTT ATA AAT ACT ACT ATT GCC AGC ATT GCT GC - #T AAA GAA GAA GGG GTA     240    Phe Ile Asn Thr Thr Ile Ala Ser Ile Ala Al - #a Lys Glu Glu Gly Val    #               225    - TCT CTA GAT AAA AGA GAG GTT GTT AGA GAG GT - #G TGC TCT GAA CAA GCT     288    Ser Leu Asp Lys Arg Glu Val Val Arg Glu Va - #l Cys Ser Glu Gln Ala    #           240    - GAG ACC GGT CCG TGC CGT GCA ATG CAC TGG CG - #C TGG TAC TTT GAC GTC     336    Glu Thr Gly Pro Cys Arg Ala Met His Trp Ar - #g Trp Tyr Phe Asp Val    #       255    - ACT GAA GGT AAG TGC GCT CCA TTC TTT TAC GG - #C GGT TGC GGC GGC AAC     384    Thr Glu Gly Lys Cys Ala Pro Phe Phe Tyr Gl - #y Gly Cys Gly Gly Asn    #   270    - CGT AAC AAC TTT GAC ACT GAA GAG TAC TGC AT - #G GCA GTG TGC GGA TCC     432    Arg Asn Asn Phe Asp Thr Glu Glu Tyr Cys Me - #t Ala Val Cys Gly Ser    275                 2 - #80                 2 - #85                 2 -    #90    #     445    Ala Ile    - (2) INFORMATION FOR SEQ ID NO:95:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 146 amino              (B) TYPE: amino acid              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:95:    - Met Arg Phe Pro Ser Ile Phe Thr Ala Val Le - #u Phe Ala Ala Ser Ser    #                 15    - Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Gl - #u Asp Glu Thr Ala Gln    #             30    - Ile Pro Ala Glu Ala Val Ile Gly Tyr Leu As - #p Leu Glu Gly Asp Phe    #         45    - Asp Val Ala Val Leu Pro Phe Ser Asn Ser Th - #r Asn Asn Gly Leu Leu    #     60    - Phe Ile Asn Thr Thr Ile Ala Ser Ile Ala Al - #a Lys Glu Glu Gly Val    # 80    - Ser Leu Asp Lys Arg Glu Val Val Arg Glu Va - #l Cys Ser Glu Gln Ala    #                 95    - Glu Thr Gly Pro Cys Arg Ala Met His Trp Ar - #g Trp Tyr Phe Asp Val    #           110    - Thr Glu Gly Lys Cys Ala Pro Phe Phe Tyr Gl - #y Gly Cys Gly Gly Asn    #       125    - Arg Asn Asn Phe Asp Thr Glu Glu Tyr Cys Me - #t Ala Val Cys Gly Ser    #   140    - Ala Ile    145    - (2) INFORMATION FOR SEQ ID NO:96:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 445 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (ix) FEATURE:              (A) NAME/KEY: CDS              (B) LOCATION: 1..438    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:96:    - ATG AGA TTT CCT TCA ATT TTT ACT GCA GTT TT - #A TTC GCA GCA TCC TCC      48    Met Arg Phe Pro Ser Ile Phe Thr Ala Val Le - #u Phe Ala Ala Ser Ser    #           160    - GCA TTA GCT GCT CCA GTC AAC ACT ACA ACA GA - #A GAT GAA ACG GCA CAA      96    Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Gl - #u Asp Glu Thr Ala Gln    #       175    - ATT CCG GCT GAA GCT GTC ATC GGT TAC TTA GA - #T TTA GAA GGG GAT TTC     144    Ile Pro Ala Glu Ala Val Ile Gly Tyr Leu As - #p Leu Glu Gly Asp Phe    #   190    - GAT GTT GCT GTT TTG CCA TTT TCC AAC AGC AC - #A AAT AAC GGG TTA TTG     192    Asp Val Ala Val Leu Pro Phe Ser Asn Ser Th - #r Asn Asn Gly Leu Leu    195                 2 - #00                 2 - #05                 2 -    #10    - TTT ATA AAT ACT ACT ATT GCC AGC ATT GCT GC - #T AAA GAA GAA GGG GTA     240    Phe Ile Asn Thr Thr Ile Ala Ser Ile Ala Al - #a Lys Glu Glu Gly Val    #               225    - TCT CTA GAT AAA AGA GAG GTT GTT AGA GAG GT - #G TGC TCT GAA CAA GCT     288    Ser Leu Asp Lys Arg Glu Val Val Arg Glu Va - #l Cys Ser Glu Gln Ala    #           240    - GAG ACC GGT CCG TGC CGT GCA GCT CAC TCC CG - #C TGG TAC TTT GAC GTC     336    Glu Thr Gly Pro Cys Arg Ala Ala His Ser Ar - #g Trp Tyr Phe Asp Val    #       255    - ACT GAA GGT AAG TGC GCT CCA TTC TTT TAC GG - #C GGT TGC GGC GGC AAC     384    Thr Glu Gly Lys Cys Ala Pro Phe Phe Tyr Gl - #y Gly Cys Gly Gly Asn    #   270    - CGT AAC AAC TTT GAC ACT GAA GAG TAC TGC AT - #G GCA GTG TGC GGA TCC     432    Arg Asn Asn Phe Asp Thr Glu Glu Tyr Cys Me - #t Ala Val Cys Gly Ser    275                 2 - #80                 2 - #85                 2 -    #90    #     445    Ala Ile    - (2) INFORMATION FOR SEQ ID NO:97:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 146 amino              (B) TYPE: amino acid              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:97:    - Met Arg Phe Pro Ser Ile Phe Thr Ala Val Le - #u Phe Ala Ala Ser Ser    #                 15    - Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Gl - #u Asp Glu Thr Ala Gln    #             30    - Ile Pro Ala Glu Ala Val Ile Gly Tyr Leu As - #p Leu Glu Gly Asp Phe    #         45    - Asp Val Ala Val Leu Pro Phe Ser Asn Ser Th - #r Asn Asn Gly Leu Leu    #     60    - Phe Ile Asn Thr Thr Ile Ala Ser Ile Ala Al - #a Lys Glu Glu Gly Val    # 80    - Ser Leu Asp Lys Arg Glu Val Val Arg Glu Va - #l Cys Ser Glu Gln Ala    #                 95    - Glu Thr Gly Pro Cys Arg Ala Ala His Ser Ar - #g Trp Tyr Phe Asp Val    #           110    - Thr Glu Gly Lys Cys Ala Pro Phe Phe Tyr Gl - #y Gly Cys Gly Gly Asn    #       125    - Arg Asn Asn Phe Asp Thr Glu Glu Tyr Cys Me - #t Ala Val Cys Gly Ser    #   140    - Ala Ile    145    - (2) INFORMATION FOR SEQ ID NO:98:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 445 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (ix) FEATURE:              (A) NAME/KEY: CDS              (B) LOCATION: 1..438    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:98:    - ATG AGA TTT CCT TCA ATT TTT ACT GCA GTT TT - #A TTC GCA GCA TCC TCC      48    Met Arg Phe Pro Ser Ile Phe Thr Ala Val Le - #u Phe Ala Ala Ser Ser    #           160    - GCA TTA GCT GCT CCA GTC AAC ACT ACA ACA GA - #A GAT GAA ACG GCA CAA      96    Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Gl - #u Asp Glu Thr Ala Gln    #       175    - ATT CCG GCT GAA GCT GTC ATC GGT TAC TTA GA - #T TTA GAA GGG GAT TTC     144    Ile Pro Ala Glu Ala Val Ile Gly Tyr Leu As - #p Leu Glu Gly Asp Phe    #   190    - GAT GTT GCT GTT TTG CCA TTT TCC AAC AGC AC - #A AAT AAC GGG TTA TTG     192    Asp Val Ala Val Leu Pro Phe Ser Asn Ser Th - #r Asn Asn Gly Leu Leu    195                 2 - #00                 2 - #05                 2 -    #10    - TTT ATA AAT ACT ACT ATT GCC AGC ATT GCT GC - #T AAA GAA GAA GGG GTA     240    Phe Ile Asn Thr Thr Ile Ala Ser Ile Ala Al - #a Lys Glu Glu Gly Val    #               225    - TCT CTA GAT AAA AGA GAG GTT GTT AGA GAG GT - #G TGC TCT GAA CAA GCT     288    Ser Leu Asp Lys Arg Glu Val Val Arg Glu Va - #l Cys Ser Glu Gln Ala    #           240    - GAG ACC GGT CCG TGC CGT GCA TTG CAC TCC CG - #C TGG TAC TTT GAC GTC     336    Glu Thr Gly Pro Cys Arg Ala Leu His Ser Ar - #g Trp Tyr Phe Asp Val    #       255    - ACT GAA GGT AAG TGC GCT CCA TTC TTT TAC GG - #C GGT TGC GGC GGC AAC     384    Thr Glu Gly Lys Cys Ala Pro Phe Phe Tyr Gl - #y Gly Cys Gly Gly Asn    #   270    - CGT AAC AAC TTT GAC ACT GAA GAG TAC TGC AT - #G GCA GTG TGC GGA TCC     432    Arg Asn Asn Phe Asp Thr Glu Glu Tyr Cys Me - #t Ala Val Cys Gly Ser    275                 2 - #80                 2 - #85                 2 -    #90    #     445    Ala Ile    - (2) INFORMATION FOR SEQ ID NO:99:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 146 amino              (B) TYPE: amino acid              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:99:    - Met Arg Phe Pro Ser Ile Phe Thr Ala Val Le - #u Phe Ala Ala Ser Ser    #                 15    - Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Gl - #u Asp Glu Thr Ala Gln    #             30    - Ile Pro Ala Glu Ala Val Ile Gly Tyr Leu As - #p Leu Glu Gly Asp Phe    #         45    - Asp Val Ala Val Leu Pro Phe Ser Asn Ser Th - #r Asn Asn Gly Leu Leu    #     60    - Phe Ile Asn Thr Thr Ile Ala Ser Ile Ala Al - #a Lys Glu Glu Gly Val    # 80    - Ser Leu Asp Lys Arg Glu Val Val Arg Glu Va - #l Cys Ser Glu Gln Ala    #                 95    - Glu Thr Gly Pro Cys Arg Ala Leu His Ser Ar - #g Trp Tyr Phe Asp Val    #           110    - Thr Glu Gly Lys Cys Ala Pro Phe Phe Tyr Gl - #y Gly Cys Gly Gly Asn    #       125    - Arg Asn Asn Phe Asp Thr Glu Glu Tyr Cys Me - #t Ala Val Cys Gly Ser    #   140    - Ala Ile    145    - (2) INFORMATION FOR SEQ ID NO:100:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 704 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (ix) FEATURE:              (A) NAME/KEY: CDS              (B) LOCATION: 1..699    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:100:    - GTG AAA CAA AGC ACT ATT GCA CTG GCA CTC TT - #A CCG TTA CTG TTT ACC      48    Val Lys Gln Ser Thr Ile Ala Leu Ala Leu Le - #u Pro Leu Leu Phe Thr    #           160    - CCG GTG ACC AAA GCC GAG GTG TGC TCT GAA CA - #A GCT GAG ACC GGT CCG      96    Pro Val Thr Lys Ala Glu Val Cys Ser Glu Gl - #n Ala Glu Thr Gly Pro    #       175    - TGC CGT GCA ATG ATC TCC CGC TGG TAC TTT GA - #C GTC ACT GAA GGT AAG     144    Cys Arg Ala Met Ile Ser Arg Trp Tyr Phe As - #p Val Thr Glu Gly Lys    #   190    - TGC GCT CCA TTC TTT TAC GGC GGT TGC GGC GG - #C AAC CGT AAC AAC TTT     192    Cys Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gl - #y Asn Arg Asn Asn Phe    195                 2 - #00                 2 - #05                 2 -    #10    - GAC ACT GAA GAG TAC TGC ATG GCA GTG TGC GG - #A TCC GGT GGT GGC TCT     240    Asp Thr Glu Glu Tyr Cys Met Ala Val Cys Gl - #y Ser Gly Gly Gly Ser    #               225    - GGT TCC GGT GAT TTT GAT TAT GAA AAG ATG GC - #A AAC GCT AAT AAG GGG     288    Gly Ser Gly Asp Phe Asp Tyr Glu Lys Met Al - #a Asn Ala Asn Lys Gly    #           240    - GCT ATG ACC GAA AAT GCC GAT GAA AAC GCG CT - #A CAG TCT GAC GCT AAA     336    Ala Met Thr Glu Asn Ala Asp Glu Asn Ala Le - #u Gln Ser Asp Ala Lys    #       255    - GGC AAA CTT GAT TCT GTC GCT ACT GAT TAC GG - #T GCT GCT ATC GAT GGT     384    Gly Lys Leu Asp Ser Val Ala Thr Asp Tyr Gl - #y Ala Ala Ile Asp Gly    #   270    - TTC ATT GGT GAC GTT TCC GGC CTT GCT AAT GG - #T AAT GGT GCT ACT GGT     432    Phe Ile Gly Asp Val Ser Gly Leu Ala Asn Gl - #y Asn Gly Ala Thr Gly    275                 2 - #80                 2 - #85                 2 -    #90    - GAT TTT GCT GGC TCT AAT TCC CAA ATG GCT CA - #A GTC GGT GAC GGT GAT     480    Asp Phe Ala Gly Ser Asn Ser Gln Met Ala Gl - #n Val Gly Asp Gly Asp    #               305    - AAT TCA CCT TTA ATG AAT AAT TTC CGT CAA TA - #T TTA CCT TCC CTC CCT     528    Asn Ser Pro Leu Met Asn Asn Phe Arg Gln Ty - #r Leu Pro Ser Leu Pro    #           320    - CAA TCG GTT GAA TGT CGC CCT TTT GTC TTT GG - #C GCT GGT AAA CCA TAC     576    Gln Ser Val Glu Cys Arg Pro Phe Val Phe Gl - #y Ala Gly Lys Pro Tyr    #       335    - GAA TTT TCT ATT GAT TGT GAC AAA ATA AAC TT - #A TTC CGT GGT GTC TTT     624    Glu Phe Ser Ile Asp Cys Asp Lys Ile Asn Le - #u Phe Arg Gly Val Phe    #   350    - GCG TTT CTT TTA TAT GTT GCC ACC TTT ATG TA - #T GTA TTT TCT ACG TTT     672    Ala Phe Leu Leu Tyr Val Ala Thr Phe Met Ty - #r Val Phe Ser Thr Phe    355                 3 - #60                 3 - #65                 3 -    #70    #         704      GT AAT AAG GAG TCT TAATA    Ala Asn Ile Leu Arg Asn Lys Glu Ser                    375    - (2) INFORMATION FOR SEQ ID NO:101:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 233 amino              (B) TYPE: amino acid              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:101:    - Val Lys Gln Ser Thr Ile Ala Leu Ala Leu Le - #u Pro Leu Leu Phe Thr    #                 15    - Pro Val Thr Lys Ala Glu Val Cys Ser Glu Gl - #n Ala Glu Thr Gly Pro    #             30    - Cys Arg Ala Met Ile Ser Arg Trp Tyr Phe As - #p Val Thr Glu Gly Lys    #         45    - Cys Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gl - #y Asn Arg Asn Asn Phe    #     60    - Asp Thr Glu Glu Tyr Cys Met Ala Val Cys Gl - #y Ser Gly Gly Gly Ser    # 80    - Gly Ser Gly Asp Phe Asp Tyr Glu Lys Met Al - #a Asn Ala Asn Lys Gly    #                 95    - Ala Met Thr Glu Asn Ala Asp Glu Asn Ala Le - #u Gln Ser Asp Ala Lys    #           110    - Gly Lys Leu Asp Ser Val Ala Thr Asp Tyr Gl - #y Ala Ala Ile Asp Gly    #       125    - Phe Ile Gly Asp Val Ser Gly Leu Ala Asn Gl - #y Asn Gly Ala Thr Gly    #   140    - Asp Phe Ala Gly Ser Asn Ser Gln Met Ala Gl - #n Val Gly Asp Gly Asp    145                 1 - #50                 1 - #55                 1 -    #60    - Asn Ser Pro Leu Met Asn Asn Phe Arg Gln Ty - #r Leu Pro Ser Leu Pro    #               175    - Gln Ser Val Glu Cys Arg Pro Phe Val Phe Gl - #y Ala Gly Lys Pro Tyr    #           190    - Glu Phe Ser Ile Asp Cys Asp Lys Ile Asn Le - #u Phe Arg Gly Val Phe    #       205    - Ala Phe Leu Leu Tyr Val Ala Thr Phe Met Ty - #r Val Phe Ser Thr Phe    #   220    - Ala Asn Ile Leu Arg Asn Lys Glu Ser    225                 2 - #30    - (2) INFORMATION FOR SEQ ID NO:102:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 701 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (ix) FEATURE:              (A) NAME/KEY: CDS              (B) LOCATION: 1..696    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:102:    - GTG AAA CAA AGC ACT ATT GCA CTG GCA CTC TT - #A CCG TTA CTG TTT ACC      48    Val Lys Gln Ser Thr Ile Ala Leu Ala Leu Le - #u Pro Leu Leu Phe Thr    #   245    - CCG GTG ACC AAA GCC GAG GTG TGC TCT GAA CA - #A GCT GAG ACC GGT CCG      96    Pro Val Thr Lys Ala Glu Val Cys Ser Glu Gl - #n Ala Glu Thr Gly Pro    250                 2 - #55                 2 - #60                 2 -    #65    - TGC CGT NNS NNS NNS NNS TGG TAC TTT GAC GT - #C ACT GAA GGT AAG TGC     144    Cys Arg Xaa Xaa Xaa Xaa Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #               280    - GCT CCA TTC TTT TAC GGC GGT TGC GGC GGC AA - #C CGT AAC AAC TTT GAC     192    Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #           295    - ACT GAA GAG TAC TGC ATG GCA GTG TGC GGA TC - #C GGT GGT GGC TCT GGT     240    Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Gly Gly Gly Ser Gly    #       310    - TCC GGT GAT TTT GAT TAT GAA AAG ATG GCA AA - #C GCT AAT AAG GGG GCT     288    Ser Gly Asp Phe Asp Tyr Glu Lys Met Ala As - #n Ala Asn Lys Gly Ala    #   325    - ATG ACC GAA AAT GCC GAT GAA AAC GCG CTA CA - #G TCT GAC GCT AAA GGC     336    Met Thr Glu Asn Ala Asp Glu Asn Ala Leu Gl - #n Ser Asp Ala Lys Gly    330                 3 - #35                 3 - #40                 3 -    #45    - AAA CTT GAT TCT GTC GCT ACT GAT TAC GGT GC - #T GCT ATC GAT GGT TTC     384    Lys Leu Asp Ser Val Ala Thr Asp Tyr Gly Al - #a Ala Ile Asp Gly Phe    #               360    - ATT GGT GAC GTT TCC GGC CTT GCT AAT GGT AA - #T GGT GCT ACT GGT GAT     432    Ile Gly Asp Val Ser Gly Leu Ala Asn Gly As - #n Gly Ala Thr Gly Asp    #           375    - TTT GCT GGC TCT AAT TCC CAA ATG GCT CAA GT - #C GGT GAC GGT GAT AAT     480    Phe Ala Gly Ser Asn Ser Gln Met Ala Gln Va - #l Gly Asp Gly Asp Asn    #       390    - TCA CCT TTA ATG AAT AAT TTC CGT CAA TAT TT - #A CCT TCC CTC CCT CAA     528    Ser Pro Leu Met Asn Asn Phe Arg Gln Tyr Le - #u Pro Ser Leu Pro Gln    #   405    - TCG GTT GAA TGT CGC CCT TTT GTC TTT GGC GC - #T GGT AAA CCA TAC GAA     576    Ser Val Glu Cys Arg Pro Phe Val Phe Gly Al - #a Gly Lys Pro Tyr Glu    410                 4 - #15                 4 - #20                 4 -    #25    - TTT TCT ATT GAT TGT GAC AAA ATA AAC TTA TT - #C CGT GGT GTC TTT GCG     624    Phe Ser Ile Asp Cys Asp Lys Ile Asn Leu Ph - #e Arg Gly Val Phe Ala    #               440    - TTT CTT TTA TAT GTT GCC ACC TTT ATG TAT GT - #A TTT TCT ACG TTT GCT     672    Phe Leu Leu Tyr Val Ala Thr Phe Met Tyr Va - #l Phe Ser Thr Phe Ala    #           455    #           701    AT AAG GAG TCT TAATA    Asn Ile Leu Arg Asn Lys Glu Ser    #       465    - (2) INFORMATION FOR SEQ ID NO:103:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 232 amino              (B) TYPE: amino acid              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:103:    - Val Lys Gln Ser Thr Ile Ala Leu Ala Leu Le - #u Pro Leu Leu Phe Thr    #                 15    - Pro Val Thr Lys Ala Glu Val Cys Ser Glu Gl - #n Ala Glu Thr Gly Pro    #             30    - Cys Arg Xaa Xaa Xaa Xaa Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #         45    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #     60    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Gly Gly Gly Ser Gly    # 80    - Ser Gly Asp Phe Asp Tyr Glu Lys Met Ala As - #n Ala Asn Lys Gly Ala    #                 95    - Met Thr Glu Asn Ala Asp Glu Asn Ala Leu Gl - #n Ser Asp Ala Lys Gly    #           110    - Lys Leu Asp Ser Val Ala Thr Asp Tyr Gly Al - #a Ala Ile Asp Gly Phe    #       125    - Ile Gly Asp Val Ser Gly Leu Ala Asn Gly As - #n Gly Ala Thr Gly Asp    #   140    - Phe Ala Gly Ser Asn Ser Gln Met Ala Gln Va - #l Gly Asp Gly Asp Asn    145                 1 - #50                 1 - #55                 1 -    #60    - Ser Pro Leu Met Asn Asn Phe Arg Gln Tyr Le - #u Pro Ser Leu Pro Gln    #               175    - Ser Val Glu Cys Arg Pro Phe Val Phe Gly Al - #a Gly Lys Pro Tyr Glu    #           190    - Phe Ser Ile Asp Cys Asp Lys Ile Asn Leu Ph - #e Arg Gly Val Phe Ala    #       205    - Phe Leu Leu Tyr Val Ala Thr Phe Met Tyr Va - #l Phe Ser Thr Phe Ala    #   220    - Asn Ile Leu Arg Asn Lys Glu Ser    225                 2 - #30    - (2) INFORMATION FOR SEQ ID NO:104:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 704 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (ix) FEATURE:              (A) NAME/KEY: CDS              (B) LOCATION: 1..699    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:104:    - GTG AAA CAA AGC ACT ATT GCA CTG GCA CTC TT - #A CCG TTA CTG TTT ACC      48    Val Lys Gln Ser Thr Ile Ala Leu Ala Leu Le - #u Pro Leu Leu Phe Thr    #       245    - CCG GTG ACC AAA GCC GAG GTG TGC TCT GAA CA - #A GCT GAG ACC GGT CCG      96    Pro Val Thr Lys Ala Glu Val Cys Ser Glu Gl - #n Ala Glu Thr Gly Pro    #   260    - TGC CGT GCA GCT ATC TTC CGC TGG TAC TTT GA - #C GTC ACT GAA GGT AAG     144    Cys Arg Ala Ala Ile Phe Arg Trp Tyr Phe As - #p Val Thr Glu Gly Lys    265                 2 - #70                 2 - #75                 2 -    #80    - TGC GCT CCA TTC TTT TAC GGC GGT TGC GGC GG - #C AAC CGT AAC AAC TTT     192    Cys Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gl - #y Asn Arg Asn Asn Phe    #               295    - GAC ACT GAA GAG TAC TGC ATG GCA GTG TGC GG - #A TCC GGT GGT GGC TCT     240    Asp Thr Glu Glu Tyr Cys Met Ala Val Cys Gl - #y Ser Gly Gly Gly Ser    #           310    - GGT TCC GGT GAT TTT GAT TAT GAA AAG ATG GC - #A AAC GCT AAT AAG GGG     288    Gly Ser Gly Asp Phe Asp Tyr Glu Lys Met Al - #a Asn Ala Asn Lys Gly    #       325    - GCT ATG ACC GAA AAT GCC GAT GAA AAC GCG CT - #A CAG TCT GAC GCT AAA     336    Ala Met Thr Glu Asn Ala Asp Glu Asn Ala Le - #u Gln Ser Asp Ala Lys    #   340    - GGC AAA CTT GAT TCT GTC GCT ACT GAT TAC GG - #T GCT GCT ATC GAT GGT     384    Gly Lys Leu Asp Ser Val Ala Thr Asp Tyr Gl - #y Ala Ala Ile Asp Gly    345                 3 - #50                 3 - #55                 3 -    #60    - TTC ATT GGT GAC GTT TCC GGC CTT GCT AAT GG - #T AAT GGT GCT ACT GGT     432    Phe Ile Gly Asp Val Ser Gly Leu Ala Asn Gl - #y Asn Gly Ala Thr Gly    #               375    - GAT TTT GCT GGC TCT AAT TCC CAA ATG GCT CA - #A GTC GGT GAC GGT GAT     480    Asp Phe Ala Gly Ser Asn Ser Gln Met Ala Gl - #n Val Gly Asp Gly Asp    #           390    - AAT TCA CCT TTA ATG AAT AAT TTC CGT CAA TA - #T TTA CCT TCC CTC CCT     528    Asn Ser Pro Leu Met Asn Asn Phe Arg Gln Ty - #r Leu Pro Ser Leu Pro    #       405    - CAA TCG GTT GAA TGT CGC CCT TTT GTC TTT GG - #C GCT GGT AAA CCA TAC     576    Gln Ser Val Glu Cys Arg Pro Phe Val Phe Gl - #y Ala Gly Lys Pro Tyr    #   420    - GAA TTT TCT ATT GAT TGT GAC AAA ATA AAC TT - #A TTC CGT GGT GTC TTT     624    Glu Phe Ser Ile Asp Cys Asp Lys Ile Asn Le - #u Phe Arg Gly Val Phe    425                 4 - #30                 4 - #35                 4 -    #40    - GCG TTT CTT TTA TAT GTT GCC ACC TTT ATG TA - #T GTA TTT TCT ACG TTT     672    Ala Phe Leu Leu Tyr Val Ala Thr Phe Met Ty - #r Val Phe Ser Thr Phe    #               455    #         704      GT AAT AAG GAG TCT TAATA    Ala Asn Ile Leu Arg Asn Lys Glu Ser    #           465    - (2) INFORMATION FOR SEQ ID NO:105:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 233 amino              (B) TYPE: amino acid              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:105:    - Val Lys Gln Ser Thr Ile Ala Leu Ala Leu Le - #u Pro Leu Leu Phe Thr    #                 15    - Pro Val Thr Lys Ala Glu Val Cys Ser Glu Gl - #n Ala Glu Thr Gly Pro    #             30    - Cys Arg Ala Ala Ile Phe Arg Trp Tyr Phe As - #p Val Thr Glu Gly Lys    #         45    - Cys Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gl - #y Asn Arg Asn Asn Phe    #     60    - Asp Thr Glu Glu Tyr Cys Met Ala Val Cys Gl - #y Ser Gly Gly Gly Ser    # 80    - Gly Ser Gly Asp Phe Asp Tyr Glu Lys Met Al - #a Asn Ala Asn Lys Gly    #                 95    - Ala Met Thr Glu Asn Ala Asp Glu Asn Ala Le - #u Gln Ser Asp Ala Lys    #           110    - Gly Lys Leu Asp Ser Val Ala Thr Asp Tyr Gl - #y Ala Ala Ile Asp Gly    #       125    - Phe Ile Gly Asp Val Ser Gly Leu Ala Asn Gl - #y Asn Gly Ala Thr Gly    #   140    - Asp Phe Ala Gly Ser Asn Ser Gln Met Ala Gl - #n Val Gly Asp Gly Asp    145                 1 - #50                 1 - #55                 1 -    #60    - Asn Ser Pro Leu Met Asn Asn Phe Arg Gln Ty - #r Leu Pro Ser Leu Pro    #               175    - Gln Ser Val Glu Cys Arg Pro Phe Val Phe Gl - #y Ala Gly Lys Pro Tyr    #           190    - Glu Phe Ser Ile Asp Cys Asp Lys Ile Asn Le - #u Phe Arg Gly Val Phe    #       205    - Ala Phe Leu Leu Tyr Val Ala Thr Phe Met Ty - #r Val Phe Ser Thr Phe    #   220    - Ala Asn Ile Leu Arg Asn Lys Glu Ser    225                 2 - #30    - (2) INFORMATION FOR SEQ ID NO:106:    -      (i) SEQUENCE CHARACTERISTICS:    #pairs    (A) LENGTH: 445 base              (B) TYPE: nucleic acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: DNA (genomic)    -     (ix) FEATURE:              (A) NAME/KEY: CDS              (B) LOCATION: 1..438    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:106:    - ATG AGA TTT CCT TCA ATT TTT ACT GCA GTT TT - #A TTC GCA GCA TCC TCC      48    Met Arg Phe Pro Ser Ile Phe Thr Ala Val Le - #u Phe Ala Ala Ser Ser    #   245    - GCA TTA GCT GCT CCA GTC AAC ACT ACA ACA GA - #A GAT GAA ACG GCA CAA      96    Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Gl - #u Asp Glu Thr Ala Gln    250                 2 - #55                 2 - #60                 2 -    #65    - ATT CCG GCT GAA GCT GTC ATC GGT TAC TTA GA - #T TTA GAA GGG GAT TTC     144    Ile Pro Ala Glu Ala Val Ile Gly Tyr Leu As - #p Leu Glu Gly Asp Phe    #               280    - GAT GTT GCT GTT TTG CCA TTT TCC AAC AGC AC - #A AAT AAC GGG TTA TTG     192    Asp Val Ala Val Leu Pro Phe Ser Asn Ser Th - #r Asn Asn Gly Leu Leu    #           295    - TTT ATA AAT ACT ACT ATT GCC AGC ATT GCT GC - #T AAA GAA GAA GGG GTA     240    Phe Ile Asn Thr Thr Ile Ala Ser Ile Ala Al - #a Lys Glu Glu Gly Val    #       310    - TCT CTA GAT AAA AGA GAG GTT GTT AGA GAG GT - #G TGC TCT GAA CAA GCT     288    Ser Leu Asp Lys Arg Glu Val Val Arg Glu Va - #l Cys Ser Glu Gln Ala    #   325    - GAG ACC GGT CCG TGC CGT GCA GCT ATC TTC CG - #C TGG TAC TTT GAC GTC     336    Glu Thr Gly Pro Cys Arg Ala Ala Ile Phe Ar - #g Trp Tyr Phe Asp Val    330                 3 - #35                 3 - #40                 3 -    #45    - ACT GAA GGT AAG TGC GCT CCA TTC TTT TAC GG - #C GGT TGC GGC GGC AAC     384    Thr Glu Gly Lys Cys Ala Pro Phe Phe Tyr Gl - #y Gly Cys Gly Gly Asn    #               360    - CGT AAC AAC TTT GAC ACT GAA GAG TAC TGC AT - #G GCA GTG TGC GGA TCC     432    Arg Asn Asn Phe Asp Thr Glu Glu Tyr Cys Me - #t Ala Val Cys Gly Ser    #           375    #     445    Ala Ile    - (2) INFORMATION FOR SEQ ID NO:107:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 146 amino              (B) TYPE: amino acid              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    #NO:107:(xi) SEQUENCE DESCRIPTION: SEQ ID    - Met Arg Phe Pro Ser Ile Phe Thr Ala Val Le - #u Phe Ala Ala Ser Ser    #                 15    - Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Gl - #u Asp Glu Thr Ala Gln    #             30    - Ile Pro Ala Glu Ala Val Ile Gly Tyr Leu As - #p Leu Glu Gly Asp Phe    #         45    - Asp Val Ala Val Leu Pro Phe Ser Asn Ser Th - #r Asn Asn Gly Leu Leu    #     60    - Phe Ile Asn Thr Thr Ile Ala Ser Ile Ala Al - #a Lys Glu Glu Gly Val    # 80    - Ser Leu Asp Lys Arg Glu Val Val Arg Glu Va - #l Cys Ser Glu Gln Ala    #                 95    - Glu Thr Gly Pro Cys Arg Ala Ala Ile Phe Ar - #g Trp Tyr Phe Asp Val    #           110    - Thr Glu Gly Lys Cys Ala Pro Phe Phe Tyr Gl - #y Gly Cys Gly Gly Asn    #       125    - Arg Asn Asn Phe Asp Thr Glu Glu Tyr Cys Me - #t Ala Val Cys Gly Ser    #   140    - Ala Ile    145    - (2) INFORMATION FOR SEQ ID NO:108:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 58 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:108:    - Arg Pro Asp Phe Cys Leu Glu Pro Pro Tyr Th - #r Gly Pro Cys Lys Ala    #                15    - Arg Ile Ile Arg Tyr Phe Tyr Asn Ala Lys Al - #a Gly Leu Cys Gln Thr    #            30    - Phe Val Tyr Gly Gly Cys Arg Ala Lys Arg As - #n Asn Phe Lys Ser Ala    #        45    - Glu Asp Cys Met Arg Thr Cys Gly Gly Ala    #    55    - (2) INFORMATION FOR SEQ ID NO:109:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 56 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:109:    - Asp Phe Cys Leu Glu Pro Pro Tyr Thr Gly Pr - #o Cys Arg Ala Arg Ile    #                15    - Ile Arg Tyr Phe Tyr Asn Ala Lys Ala Gly Le - #u Cys Gln Thr Phe Val    #            30    - Tyr Gly Gly Cys Arg Ala Lys Ser Asn Asn Ph - #e Lys Ser Ala Glu Asp    #        45    - Cys Met Arg Thr Cys Gly Gly Ala    #    55    - (2) INFORMATION FOR SEQ ID NO:110:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:110:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:111:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:111:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Pro Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:112:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:112:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Val Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:113:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:113:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Ser Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:114:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 57 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:114:    - Glu Val Cys Ser Glu Gln Ala Glu Thr Gly Pr - #o Cys Lys Ala Met Ile    #                15    - Ser Arg Trp Tyr Phe Asp Val Thr Glu Gly Ly - #s Cys Ala Pro Phe Phe    #            30    - Tyr Gly Gly Cys Gly Gly Asn Arg Asn Asn Ph - #e Asp Thr Glu Glu Tyr    #        45    - Cys Met Ala Val Cys Gly Ser Ala Ile    #    55    - (2) INFORMATION FOR SEQ ID NO:115:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:115:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Gly Met Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:116:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 57 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:116:    - Glu Val Cys Ser Glu Gln Ala Glu Thr Gly Pr - #o Cys Arg Ala Arg Ile    #                15    - Ser Arg Trp Tyr Phe Asp Val Thr Glu Gly Ly - #s Cys Ala Pro Phe Phe    #            30    - Tyr Gly Gly Cys Gly Gly Asn Arg Asn Asn Ph - #e Asp Thr Glu Glu Tyr    #        45    - Cys Met Ala Val Cys Gly Ser Ala Ile    #    55    - (2) INFORMATION FOR SEQ ID NO:117:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:117:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Ala Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:118:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:118:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Ile Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:119:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:119:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Leu Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:120:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:120:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Ser Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:121:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:121:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Val Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:122:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:122:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Gly Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:123:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:123:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met His Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:124:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:124:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ala Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:125:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:125:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Phe Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:126:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:126:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Lys Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:127:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:127:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Leu Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:128:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 57 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:128:    - Glu Val Cys Ser Glu Gln Ala Glu Thr Gly Pr - #o Cys Arg Ala Met Ile    #                15    - Ile Arg Trp Tyr Phe Asp Val Thr Glu Gly Ly - #s Cys Ala Pro Phe Phe    #            30    - Tyr Gly Gly Cys Gly Gly Asn Arg Asn Asn Ph - #e Asp Thr Glu Glu Tyr    #        45    - Cys Met Ala Val Cys Gly Ser Ala Ile    #    55    - (2) INFORMATION FOR SEQ ID NO:129:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:129:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Pro Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:130:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:130:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Phe Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:131:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:131:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Tyr Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:132:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:132:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Trp Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:133:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:133:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Leu Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:134:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:134:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile His Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:135:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:135:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Glu Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:136:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:136:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Gln Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:137:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:137:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Ala Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:138:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:138:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Thr Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:139:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:139:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Ser His Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:140:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:140:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Lys Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:141:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:141:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Leu Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:142:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:142:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Val Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:143:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:143:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Leu Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:144:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:144:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Gly Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:145:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:145:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Ala Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:146:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:146:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Lys Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:147:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:147:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Leu Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:148:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:148:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Met Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:149:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:149:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Asn Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:150:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:150:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Pro Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:151:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:151:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gln Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:152:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 57 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:152:    - Glu Val Cys Ser Glu Gln Ala Glu Thr Gly Pr - #o Cys Arg Ala Met Ile    #                15    - Ser Arg Trp Tyr Phe Asp Val Thr Glu Gly Ly - #s Cys Ala Pro Phe Phe    #            30    - Tyr Gly Gly Cys Arg Gly Asn Arg Asn Asn Ph - #e Asp Thr Glu Glu Tyr    #        45    - Cys Met Ala Val Cys Gly Ser Ala Ile    #    55    - (2) INFORMATION FOR SEQ ID NO:153:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:153:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Cys Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:154:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:154:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Ser Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:155:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:155:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Thr Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:156:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:156:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Val Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:157:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:157:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Tyr Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:158:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:158:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Asp Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:159:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:159:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Glu Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:160:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:160:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys His Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:161:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:161:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Ile Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:162:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 57 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:162:    - Glu Val Cys Ser Glu Gln Ala Glu Thr Gly Pr - #o Cys Arg Ala Met Ile    #                15    - Ser Arg Trp Tyr Phe Asp Val Thr Glu Gly Ly - #s Cys Ala Pro Phe Phe    #            30    - Tyr Gly Gly Cys Gly Ala Asn Arg Asn Asn Ph - #e Asp Thr Glu Glu Tyr    #        45    - Cys Met Ala Val Cys Gly Ser Ala Ile    #    55    - (2) INFORMATION FOR SEQ ID NO:163:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:163:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Arg As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:164:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:164:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly Al - #a Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:165:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 57 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:165:    - Glu Val Cys Ser Glu Gln Ala Glu Thr Gly Pr - #o Cys Arg Ala Met Ile    #                15    - Ser Arg Trp Tyr Phe Asp Val Thr Glu Gly Ly - #s Cys Ala Pro Phe Phe    #            30    - Tyr Gly Gly Cys Gly Gly Asn Ser Asn Asn Ph - #e Asp Thr Glu Glu Tyr    #        45    - Cys Met Ala Val Cys Gly Ser Ala Ile    #    55    - (2) INFORMATION FOR SEQ ID NO:166:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:166:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Ala Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:167:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:167:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Ala His Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:168:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:168:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Leu His Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:169:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:169:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Leu Leu Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:170:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:170:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Leu Phe Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:171:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:171:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Ala Ile Phe Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:172:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:172:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Ala Ile Trp Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:173:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:173:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Ala Ile Tyr Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:174:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:174:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Leu Ile Tyr Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:175:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:175:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Leu Ile Leu Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:176:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:176:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Leu Ile Pro Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:177:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:177:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Leu Ile Phe Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:178:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:178:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Gly Ile Tyr Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:179:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:179:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Gly Ile Trp Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:180:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:180:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Gly Ile Pro Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:181:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:181:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Ala Ile Ser Ala Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:182:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:182:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Leu Ile Ser Ala Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:183:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:183:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Ala Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Arg Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:184:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:184:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Ala Ile Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Tyr Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:185:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:185:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met His Phe Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:186:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:186:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met His Tyr Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:187:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:187:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met His Trp Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:188:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:188:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Leu His Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:189:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:189:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met His Ser Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Tyr Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:190:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:190:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Phe Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Tyr Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:191:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:191:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Tyr Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Tyr Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:192:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:192:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Met Ile Trp Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Tyr Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:193:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:193:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Pro Gly Pro Cys    #                15    - Arg Ala Leu Ile Leu Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:194:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:194:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Gly Tyr Ile Thr Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:195:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:195:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Leu His Asn Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:196:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:196:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Ala His Phe Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:197:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:197:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Leu His Phe Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:198:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:198:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Ala Leu Phe Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:199:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:199:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Leu Phe Thr Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:200:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:200:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Leu Phe Lys Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:201:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:201:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Phe Phe Lys Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:202:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:202:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Ala Phe Ser Ala Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:203:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:203:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Leu Leu Ser Ala Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:204:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:204:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Leu Ile Trp His Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:205:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:205:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Leu Ile Phe Ala Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:206:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:206:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Leu Ile Tyr His Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:207:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:207:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Ala Ile His Lys Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:208:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:208:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Ala Ile Tyr His Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:209:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:209:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Leu Ile Gln His Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:210:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:210:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Leu Ile Tyr Lys Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:211:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:211:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Ala Ile Gln His Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:212:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:212:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Ala Ile Phe Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Arg Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:213:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:213:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Ala Ile Phe Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Tyr Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:214:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:214:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Leu Ile Pro Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Arg Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:215:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:215:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Val Gly Pro Cys    #                15    - Arg Ala Leu Ile Tyr His Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:216:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:216:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Ser Gly Pro Cys    #                15    - Arg Ala Leu Ile Tyr His Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:217:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:217:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Val Gly Pro Cys    #                15    - Arg Ala Ala Ile Tyr His Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:218:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:218:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Ser Gly Pro Cys    #                15    - Arg Ala Ala Ile Tyr His Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:219:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:219:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Ile Gly Pro Cys    #                15    - Arg Ala Leu Ile Tyr His Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:220:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:220:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Gly Ala Ile Gln His Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:221:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:221:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Gly Ala Ile Arg His Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:222:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:222:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Gly Ser Ile Arg His Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:223:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:223:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Gly Leu Ile Tyr His Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:224:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:224:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Gly Ala Ile Tyr His Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Gly Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:225:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:225:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Leu His Asn Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Arg Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:226:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:226:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Leu Phe Lys Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Tyr Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:227:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:227:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Leu Phe Lys Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Leu Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    - (2) INFORMATION FOR SEQ ID NO:228:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 61 amino              (B) TYPE: amino acid              (C) STRANDEDNESS: single              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: protein    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:228:    - Glu Val Val Arg Glu Val Cys Ser Glu Gln Al - #a Glu Thr Gly Pro Cys    #                15    - Arg Ala Leu Phe Lys Arg Trp Tyr Phe Asp Va - #l Thr Glu Gly Lys Cys    #            30    - Ala Pro Phe Phe Tyr Gly Gly Cys Met Gly As - #n Arg Asn Asn Phe Asp    #        45    - Thr Glu Glu Tyr Cys Met Ala Val Cys Gly Se - #r Ala Ile    #    60    __________________________________________________________________________

What is claimed is:
 1. An isolated DNA molecule comprising a DNAsequence encoding a kallikrein inhibitor comprising the sequence(SEQ IDNO:1):X¹ -Val-Cys-Ser-Glu-Gln-Ala-Glu-X² -Gly-X³ -Cys-Arg-Ala-X⁴ -X⁵ -X⁶-X⁷ -Trp-Tyr-Phe-Asp-Val-Thr-Glu-Gly-Lys-Cys-Ala-Pro-Phe-X⁸-Tyr-Gly-Gly-Cys-X⁹ -X¹⁰ -X¹¹ -X¹²-Asn-Asn-Phe-Asp-Thr-Glu-Glu-Tyr-Cys-Met-Ala-Val-Cys-Gly-Ser-Ala-Ile,wherein:X¹ is selected from Glu-Val-Val-Arg-Glu-(SEQ ID NO:2), Asp, or Glu; X²is selected from Thr, Val, Ile and Ser; X³ is selected from Pro and Ala;X⁴ is selected from Arg, Ala, Leu, Gly, or Met; X⁵ is selected from Ile,His, Leu, Lys, Ala, or Phe; X⁶ is selected from Ser, Ile, Pro, Phe, Tyr,Trp, Asn, Leu, His, Lys, or Glu; X⁷ is selected from Arg, His, or Ala;X⁸ is selected from Phe, Val, Leu, or Gly; X⁹ is selected from Gly, Ala,Lys, Pro, Arg, Leu, Met, or Tyr; X¹⁰ is selected from Ala, Arg, or Gly;X¹¹ is selected from Lys, Ala, or Asn; X¹² is selected from Ser, Ala, orArg;provided that: when X⁴ is Arg, X⁶ is Ile; when X⁹ is Arg, X⁴ is Alaor Leu; when X⁹ is Tyr, X⁴ is Ala or X⁵ is His; and either X⁵ is notIle; or X⁶ is not Ser; or X⁹ is not Gly, Leu, Phe, Met, Tyr, or Asn; orX¹⁰ is not Gly; or X¹¹ is not Asn; or X¹² is not Arg.
 2. An isolated DNAmolecule according to claim 1, operably linked to a regulatory sequencethat controls expression of the coding sequence in a host cell.
 3. Anisolated DNA molecule according to claim 2, further comprising a DNAsequence encoding a secretory signal peptide.
 4. An isolated DNAmolecule according to claim 3, where said secretory signal peptidecomprises the signal sequence of yeast alpha-mating factor.
 5. A hostcell transformed with a DNA molecule according to claim
 1. 6. A hostcell according to claim 5, wherein said host cell is E. coli or a yeastcell.
 7. A host cell according to claim 6, wherein said host cell isSaccharomyces cerevisiae.
 8. A method for producing a kallikreininhibitor, comprising the steps of culturing a host cell according toclaim 5 and isolating and purifying said inhibitor.
 9. An isolated DNAmolecule comprising a sequence encoding a kallikrein inhibitorcomprising the sequence(SEQ ID NO:2):X¹-Val-Cys-Ser-Glu-Gln-Ala-Glu-Thr-Gly-Pro-Cys-Arg-Ala-X² -X³ -X⁴-Arg-Trp-Tyr-Phe-Asp-Val-Thr-Glu-Gly-Lys-Cys-Ala-Pro-Phe-Phe-Tyr-Gly-Gly-Cys-X⁵-Gly-Asn-Arg-Asn-Asn-Phe-Asp-Thr-Glu-Glu-Tyr-Cys-Met-Ala-Val-Cys-Gly-Ser-Ala-Ile,wherein:X¹ is selected from Glu-Val-Val-Arg-Glu-(SEQ ID NO:2), Asp, or Glu; X²is selected from Ala, Leu, Gly, or Met; X³ is selected from Ile, His,Leu, Lys, Ala, or Phe; X⁴ is selected from Ser, Ile, Pro, Phe, Tyr, Trp,Asn, Leu, His, Lys, or Glu; X⁵ is selected from Gly, Ala, Lys, Pro, Arg,Leu, Met, or Tyr;provided that: when X⁵ is Arg, X² is Ala or Leu; whenX⁵ is Tyr, X² is Ala or X³ is His; and either X³ is not Ile; or X⁴ isnot Ser; or X⁵ is not Gly, Leu, Phe, Met, Tyr, or Asn.
 10. An isolatedDNA molecule according to claim 9, operably linked to a regulatorysequence that controls expression of the coding sequence in a host cell.11. An isolated DNA molecule according to claim 10, further comprising aDNA sequence encoding a secretory signal peptide.
 12. An isolated DNAmolecule according to claim 11, where said secretory signal peptidecomprises the signal sequence of yeast alpha-mating factor.
 13. A hostcell transformed with a DNA molecule according to claim
 9. 14. A hostcell according to claim 13, wherein said host cell is E. coli or a yeastcell.
 15. A host cell according to claim 14, wherein said host cell isSaccharomyces cerevisiae.
 16. A method for producing a kallikreininhibitor, comprising the steps of culturing a host cell according toclaim 13 and isolating and purifying said inhibitor.
 17. An isolated DNAmolecule comprising a DNA sequence encoding a kallikrein inhibitorcomprising the sequence(SEQ IDNO:4):Glu-Val-Val-Arg-Glu-Val-Cys-Ser-Glu-Gln-Ala-Glu-Thr-Gly-Pro-Cys-Arg-Ala-X.sup.1-X² -X³-Arg-Trp-Tyr-Phe-Asp-Val-Thr-Glu-Gly-Lys-Cys-Ala-Pro-Phe-Phe-Tyr-Gly-Gly-Cys-X⁴-Gly-Asn-Arg-Asn-Asn-Phe-Asp-Thr-Glu-Glu-Tyr-Cys-Met-Ala-Val-Cys-Gly-Ser-Ala-Ile,wherein:X¹ is selected from Ala, Leu, Gly, or Met; X² is selected from Ile, His,Leu, Lys, Ala, or Phe; X³ is selected from Ser, Ile, Pro, Phe, Tyr, Trp,Asn, Leu, His, Lys, or Glu; X⁴ is selected from Gly, Arg, Leu, Met, orTyr;provided that: when X¹ is Ala, X² is Ile, His, or Leu; when X¹ isLeu, X² is Ile or His; when X¹ is Leu and X² is Ile, X³ is not Ser; whenX¹ is Gly, X² is Ile; when X⁴ is Arg, X¹ is Ala or Leu; when X⁴ is Tyr,X¹ is Ala or X² is His; and either X¹ is not Met, or X² is not Ile, orX³ is not Ser, or X⁴ is not Gly.
 18. An isolated DNA molecule accordingto claim 17, operably linked to a regulatory sequence that controlsexpression of the coding sequence in a host cell.
 19. An isolated DNAmolecule according to claim 18, further comprising a DNA sequenceencoding a secretory signal peptide.
 20. An isolated DNA moleculeaccording to claim 19, where said secretory signal peptide comprises thesignal sequence of yeast alpha-mating factor.
 21. A host celltransformed with a DNA molecule according to claim
 17. 22. A host cellaccording to claim 21, wherein said host cell is E. coli or a yeastcell.
 23. A host cell according to claim 22, wherein said host cell isSaccharomyces cerevisiae.
 24. A method for producing a kallikreininhibitor, comprising the steps of culturing a host cell according toclaim 21 and isolating and purifying said inhibitor.
 25. An isolated DNAmolecule comprising a DNA sequence encoding a kallikrein inhibitorcomprising the sequence(SEQ ID NO:5):X¹ -Val-Cys-Ser-Glu-Gln-Ala-Glu-X²-Gly-Pro-Cys-Arg-Ala-X³ -X⁴ -X⁵ -X⁶-Arg-Trp-Tyr-Phe-Asp-Val-Thr-Glu-Gly-Lys-Cys-Ala-Pro-Phe-Phe-Tyr-Gly-Gly-Cys-X⁷-Gly-Asn-Arg-Asn-Asn-Phe-Asp-Thr-Glu-Glu-Tyr-Cys-Met-Ala-Val-Cys-Gly-Ser-Ala-Ile,wherein:X¹ is selected from Glu-Val-Val-Arg-Glu-(SEQ ID NO:2), Asp, or Glu; X²is selected from Thr, Val, Ile and Ser; X³ is selected from Arg, Ala,Leu, Gly, or Met; X⁴ is selected from Ile, His, Leu, Lys, Ala, or Phe;X⁵ is selected from Ser, Ile, Pro, Phe, Tyr, Trp, Asn, Leu, His, Lys, orGlu; X⁶ is selected from Arg, His, or Ala; and X⁷ is selected from Gly,Ala, Lys, Pro, Arg, Leu, Met, or Tyr, and either X⁴ is not Ile; or X⁵ isnot Ser; or X⁷ is not Gly, Leu, Phe, Met, Tyr, or Asn.
 26. An isolatedDNA molecule according to claim 25, operably linked to a regulatorysequence that controls expression of the coding sequence in a host cell.27. An isolated DNA molecule according to claim 26, further comprising aDNA sequence encoding a secretory signal peptide.
 28. An isolated DNAmolecule according to claim 27, where said secretory signal peptidecomprises the signal sequence of yeast alpha-mating factor.
 29. A hostcell transformed with a DNA molecule according to claim
 25. 30. A hostcell according to claim 29, wherein said host cell is E. coli or a yeastcell.
 31. A host cell according to claim 30, wherein said host cell isSaccharomyces cerevisiae.
 32. A method for producing a kallikreininhibitor, comprising the steps of culturing a host cell according toclaim 29 and isolating and purifying said inhibitor.